Anti-TREM2 antibodies and methods of use thereof

ABSTRACT

The present disclosure is generally directed to compositions that include antibodies, e.g., monoclonal, antibodies, antibody fragments, etc., that specifically bind a TREM2 protein, e.g., a mammalian TREM2 or human TREM2, and use of such compositions in preventing, reducing risk, or treating an individual in need thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/541,019, filed Aug. 3, 2017 and 62/636,095 filed Feb. 27, 2018, whichare hereby incorporated by reference in their entirety.

SUBMISSION OF SEQUENCE LISTING ON ASCII TEXT FILE

The content of the following submission on ASCII text file isincorporated herein by reference in its entirety: a computer readableform (CRF) of the Sequence Listing (file name: 735022001800SEQLIST.TXT,date recorded: Aug. 2, 2018, size: 238 KB).

FIELD OF THE PRESENT DISCLOSURE

The present disclosure relates to anti-TREM2 antibodies and therapeuticuses of such antibodies.

BACKGROUND OF THE PRESENT DISCLOSURE

Triggering receptor expressed on myeloid cells-2 (TREM2) is animmunoglobulin-like receptor that is expressed, for example, on myeloidlineage cells.

TREM2 activity has been implicated in diseases, disorders, andconditions, such as frontotemporal dementia (FTD), Alzheimer's disease,Parkinson's disease, stroke/ischemic brain injury, multiple sclerosis,and Nasu-Hakola disease (Neumann, H et al., (2007) J Neuroimmunol 184:92-99; Takahashi, K et al., (2005) J Exp Med 201: 647-657; Takahashi, Ket al., (2007) PLoS Med 4: e124; and Hsieh, C L et al., (2009) JNeurochem 109: 1144-1156; Malm, T M et al, Neurotherapeutics. 2014 Nov.18; Paloneva, J et al., (2002) Am J Hum Genet 71: 656-662; and Paloneva,J et al., (2003) J Exp Med 198: 669-675; Guerreiro, R J et al., (2013)JAMA Neurol 70: 78-84; Guerreiro, R J et al., (2012) Arch Neurol: 1-7;Guerreiro, R et al., (2013) N Engl J Med 368: 117-127; Jonsson, T etal., (2013) N Engl J Med 368: 107-116; and Neumann, H et al., (2013) NEngl J Med 368: 182-184; and Wang Y, Cell. 2015; 160(6):1061-71).

Accordingly, there is a need for therapeutic anti-TREM2 antibodies totreat diseases, disorders, and conditions associated with decreasedTREM2 activity.

All references cited herein, including patent applications andpublications, are hereby incorporated by reference in their entirety.

SUMMARY OF THE PRESENT DISCLOSURE

The present disclosure is generally directed to compositions thatinclude antibodies, e.g., monoclonal, chimeric, humanized antibodies,antibody fragments, etc., that specifically bind a TREM2 protein, e.g.,a mammalian TREM2 (e.g., any non-human mammal) or human TREM2, and tomethods of using such compositions.

Certain aspects of the present disclosure are based, at least in part,on the identification of anti-TREM2 antibodies with improved affinityand functional characteristics. Surprisingly, the functionalcharacteristics of the anti-TREM2 antibodies were not predictable fromthe increase in affinity. In some embodiments, anti-TREM2 antibodies ofthe present disclosure bind both human and cynomolgus monkey TREM2 withan affinity that is at least about 1-fold higher than an anti-TREM2antibody selected from anti-TREM2 antibody comprising a heavy chainvariable region comprising the amino acid sequence of SEQ ID NO: 27 anda light chain variable region comprising the amino acid sequence of SEQID NO: 56 (e.g., antibody AL2p-h50); an anti-TREM2 antibody comprising aheavy chain variable region comprising the amino acid sequence of SEQ IDNO: 91 and a light chain variable region comprising the amino acidsequence of SEQ ID NO: 103 (e.g., antibody AL2p-h77); and an anti-TREM2antibody comprising a heavy chain variable region comprising the aminoacid sequence of SEQ ID NO: 119 and a light chain variable regioncomprising the amino acid sequence of SEQ ID NO: 120 (e.g., antibodyAL2). In some embodiments, anti-TREM2 antibodies of the presentdisclosure bind to primary human immune cells with an affinity that isat least about 10 times higher than that of an anti-TREM2 antibodyselected from an anti-TREM2 antibody comprising a heavy chain variableregion comprising the amino acid sequence of SEQ ID NO: 27 and a lightchain variable region comprising the amino acid sequence of SEQ ID NO:56; an anti-TREM2 antibody comprising a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO: 91 and a light chainvariable region comprising the amino acid sequence of SEQ ID NO: 103;and an anti-TREM2 antibody comprising a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO: 119 and a light chainvariable region comprising the amino acid sequence of SEQ ID NO: 120. Insome embodiments, anti-TREM2 antibodies of the present disclosurecluster and activate TREM2 signaling in an amount that is at least about1-fold greater than that of an anti-TREM2 antibody selected from ananti-TREM2 antibody comprising a heavy chain variable region comprisingthe amino acid sequence of SEQ ID NO: 27 and a light chain variableregion comprising the amino acid sequence of SEQ ID NO: 56; ananti-TREM2 antibody comprising a heavy chain variable region comprisingthe amino acid sequence of SEQ ID NO: 91 and a light chain variableregion comprising the amino acid sequence of SEQ ID NO: 103; and ananti-TREM2 antibody comprising a heavy chain variable region comprisingthe amino acid sequence of SEQ ID NO: 119 and a light chain variableregion comprising the amino acid sequence of SEQ ID NO: 120. In someembodiments, anti-TREM2 antibodies of the present disclosure increaseimmune cell survival in vitro that to an extent that is greater than ananti-TREM2 antibody selected from an anti-TREM2 antibody comprising aheavy chain variable region comprising the amino acid sequence of SEQ IDNO: 27 and a light chain variable region comprising the amino acidsequence of SEQ ID NO: 56; an anti-TREM2 antibody comprising a heavychain variable region comprising the amino acid sequence of SEQ ID NO:91 and a light chain variable region comprising the amino acid sequenceof SEQ ID NO: 103; and an anti-TREM2 antibody comprising a heavy chainvariable region comprising the amino acid sequence of SEQ ID NO: 119 anda light chain variable region comprising the amino acid sequence of SEQID NO: 120. In some embodiments, anti-TREM2 antibodies of the presentdisclosure may also have improved in vivo half-lives. In someembodiments, anti-TREM2 antibodies of the present disclosure may alsodecreases plasma levels of soluble TREM2 in vivo. In some embodiments,anti-TREM2 antibodies of the present disclosure may also decreasesoluble TREM2. In some embodiments, the soluble TREM2 is decreased aboutany of 10, 20, 30, 40, 50 or 60%.

Accordingly, certain aspects of the present disclosure relate to relateto an antibody that binds to a TREM2 protein, wherein the antibodycomprises a heavy chain variable region and a light chain variableregion, wherein the heavy chain variable region comprises: an HVR-H1comprising the sequence according to Formula I: YAFX₁X₂X₃WMN, wherein X₁is S or W, X₂ is S, L, or R, and X₃ is S, D, H, Q, or E (SEQ ID NO:121); an HVR-H2 comprising the sequence according to Formula II:RIYPGX₁GX₂TNYAX₃KX₄X₅G, wherein X₁ is D, G, E, Q, or V, X₂ is D or Q, X₃is Q, R, H, W, Y, or G, X₄ is F, R, or W, and X₅ is Q, R, K, or H (SEQID NO: 122); and an HVR-H3 comprising the sequence according to FormulaIII: ARLLRNX₁PGX₂SYAX₃DY, wherein X₁ is Q or K, X₂ is E, S, or A, and X₃is M or H (SEQ ID NO: 123), and wherein the antibody is not an antibodycomprising a heavy chain variable region comprising an HVR-H1 comprisingthe sequence of YAFSSSWMN (SEQ ID NO: 124), an HVR-H2 comprising thesequence of RIYPGDGDTNYAQKFQG (SEQ ID NO: 125), and an HVR-H3 comprisingthe sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126). Other aspects of thepresent disclosure relate to an antibody that binds to a TREM2 protein,wherein the antibody comprises a heavy chain variable region and a lightchain variable region, wherein the light chain variable regioncomprises: an HVR-L1 comprising the sequence according to Formula IV:RX₁SX₂SLX₃HSNX₄YTYLH, wherein X₁ is S or T, X₂ is Q, R, or S, X₃ is V orI, and X₄ is G, R, W, Q, or A (SEQ ID NO: 127); an HVR-L2 comprising thesequence according to Formula V: KVSNRX₁S, wherein X₁ is F, R, V, or K(SEQ ID NO: 128); and an HVR-L3 comprising the sequence according toFormula V: SQSTRVPYT (SEQ ID NO: 129), and wherein the antibody is notan antibody comprising a light chain variable region comprising anHVR-L1 comprising the sequence of RSSQSLVHSNGYTYLH (SEQ ID NO: 130), anHVR-L2 comprising the sequence of KVSNRFS (SEQ ID NO: 131), and anHVR-L3 comprising the sequence of SQSTRVPYT (SEQ ID NO: 129). Otheraspects of the present disclosure relate to an antibody that binds to aTREM2 protein, wherein the antibody comprises a heavy chain variableregion and a light chain variable region, wherein the heavy chainvariable region comprises: an HVR-H1 comprising the sequence accordingto Formula I: YAFX₁X₂X₃WMN, wherein X₁ is S or W, X₂ is S, L, or R, andX₃ is S, D, H, Q, or E (SEQ ID NO: 121); an HVR-H2 comprising thesequence according to Formula II: RIYPGX₁GX₂TNYAX₃KX₄X₅G, wherein X₁ isD, G, E, Q, or V, X₂ is D or Q, X₃ is Q, R, H, W, Y, or G, X₄ is F, R,or W, and X₅ is Q, R, K, or H (SEQ ID NO: 122); and an HVR-H3 comprisingthe sequence according to Formula III: ARLLRNX₁PGX₂SYAX₃DY, wherein X₁is Q or K, X₂ is E, S, or A, and X₃ is M or H (SEQ ID NO: 123), and thelight chain variable region comprises: an HVR-L1 comprising the sequenceaccording to Formula IV: RX₁SX₂SLX₃HSNX₄YTYLH, wherein X₁ is S or T, X₂is Q, R, or S, X₃ is V or I, and X₄ is G, R, W, Q, or A (SEQ ID NO:127); an HVR-L2 comprising the sequence according to Formula V:KVSNRX₁S, wherein X₁ is F, R, V, or K (SEQ ID NO: 128); and an HVR-L3comprising the sequence: SQSTRVPYT (SEQ ID NO: 129), and wherein theantibody is not an antibody comprising a heavy chain variable regioncomprising an HVR-H1 comprising the sequence of YAFSSSWMN (SEQ ID NO:124), an HVR-H2 comprising the sequence of RIYPGDGDTNYAQKFQG (SEQ ID NO:125), and an HVR-H3 comprising the sequence of ARLLRNQPGESYAMDY (SEQ IDNO: 126), and comprising a light chain variable region comprising anHVR-L1 comprising the sequence of RSSQSLVHSNGYTYLH (SEQ ID NO: 130), anHVR-L2 comprising the sequence of KVSNRFS (SEQ ID NO: 131), and anHVR-L3 comprising the sequence of SQSTRVPYT (SEQ ID NO: 129).

Other aspects of the present disclosure relate to an antibody that bindsto a TREM2 protein, wherein the antibody comprises a heavy chainvariable region and a light chain variable region, wherein the heavychain variable region comprises: an HVR-H1 comprising a sequenceselected from the group consisting of SEQ ID Nos: 132 and 136; an HVR-H2comprising a sequence selected from the group consisting of SEQ ID Nos:133, 135, 137, and 141; and an HVR-H3 comprising a sequence selectedfrom the group consisting of SEQ ID Nos: 126 and 138; and/or the lightthe light chain variable region comprises: an HVR-L1 comprising asequence selected from the group consisting of 130, 139, 142, and 144;an HVR-L2 comprising a sequence selected from the group consisting ofSEQ ID Nos: 131, 134, and 140; and an HVR-L3 comprising the sequence ofSEQ ID NO: 129. Other aspects of the present disclosure relate to anantibody that binds to a TREM2 protein, wherein the antibody comprises aheavy chain variable region and a light chain variable region, whereinthe heavy chain variable region comprises: an HVR-H1 comprising thesequence of SEQ ID No: 132; an HVR-H2 comprising a sequence selectedfrom the group consisting of SEQ ID Nos: 133, 135, and 141; and anHVR-H3 comprising the sequence of SEQ ID No: 126; and/or the light thelight chain variable region comprises: an HVR-L1 comprising a sequenceselected from the group consisting of 130, 142, and 144; an HVR-L2comprising a sequence selected from the group consisting of SEQ ID Nos:131 and 134; and an HVR-L3 comprising the sequence of SEQ ID NO: 129.

Other aspects of the present disclosure relate to an antibody that bindsto a TREM2 protein, wherein the antibody comprises a heavy chainvariable region and a light chain variable region, wherein the heavychain variable region comprises the HVR-H1, HVR-H2, and HVR-H3 ofantibody AL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10,AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18,AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26,AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-35, AL2p-36,AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44,AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52,AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60,AL2p-61, or AL2p-62 (as shown in Tables 2A to 2C). Other aspects of thepresent disclosure relate to an antibody that binds to a TREM2 protein,wherein the antibody comprises a heavy chain variable region and a lightchain variable region, wherein the light chain variable region comprisesthe HVR-L1, HVR-L2, and HVR-L3 of antibody AL2p-5, AL2p-6, AL2p-7,AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15,AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23,AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31,AL2p-32, AL2p-33, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43,AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51,AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59,AL2p-60, AL2p-61, or AL2p-62 (as shown in Tables 3A to 3C). Otheraspects of the present disclosure relate to an antibody that binds to aTREM2 protein, wherein the antibody comprises a heavy chain variableregion and a light chain variable region, wherein the heavy chainvariable region comprises the HVR-H1, HVR-H2, and HVR-H3 of antibodyAL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11,AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19,AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27,AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-35, AL2p-36, AL2p-37,AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45,AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53,AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61,or AL2p-62 (as shown in Tables 2A to 2C); and the light chain variableregion comprises the HVR-L1, HVR-L2, and HVR-L3 of antibody AL2p-5,AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13,AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21,AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29,AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-38, AL2p-39, AL2p-40, AL2p-41,AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49,AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57,AL2p-58, AL2p-59, AL2p-60, AL2p-61, or AL2p-62 (as shown in Tables 3A to3C). Other aspects of the present disclosure relate to an antibody thatbinds to a TREM2 protein, wherein the antibody comprises a heavy chainvariable region comprising an HVR-H1, HVR-H2, and HVR-H3 and a lightchain variable region comprising an HVR-L1, HVR-L2, and HVR-L3, whereinthe antibody comprises the HVR-H1, HVR-H2, HVR-H3, HVR-L1, HVR-L2, andHVR-L3 of antibody AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7,AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15,AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23,AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31,AL2p-32, AL2p-33, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40,AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48,AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56,AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, or AL2p-62 (as shown inTables 2A to 2C and 3A to 3C).

In some embodiments that may be combined with any of the precedingembodiments, the heavy chain variable region comprises one, two, threeor four frame work regions selected from VH FR1, VH FR2, VH FR3, and VHFR4, wherein: the VH FR1 comprises a sequence selected from the groupconsisting of SEQ ID NOs: 9-11, the VH FR2 comprises a sequence selectedfrom the group consisting of SEQ ID NOs: 12 and 13, the VH FR3 comprisesa sequence selected from the group consisting of SEQ ID NOs: 14 and 15,and the VH FR4 comprises the sequence of SEQ ID NO: 16; and/or the lightchain variable region comprises one, two, three or four frame workregions selected from VL FR1, VL FR2, VL FR3, and VL FR4, wherein: theVL FR1 comprises a sequence selected from the group consisting of SEQ IDNOs: 17-20, the VL FR2 comprises a sequence selected from the groupconsisting of SEQ ID NOs: 21 and 22, the VL FR3 comprises a sequenceselected from the group consisting of SEQ ID NOs: 23 and 24, and the VLFR4 comprises a sequence selected from the group consisting of SEQ IDNOs: 25 and 26. In some embodiments that may be combined with any of thepreceding embodiments, the antibody comprises a heavy chain variableregion comprising an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 27-71 and 91; and/or a light chain variableregion comprising an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 92-113 and 118. In some embodiments that maybe combined with any of the preceding embodiments, the antibodycomprises the heavy chain variable region of antibody AL2p-h50, AL2p-2,AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10,AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18,AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26,AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77,AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42,AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50,AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58,AL2p-59, AL2p-60, AL2p-61, or AL2p-62 (as shown in Table 6A); and/or theantibody comprises the light chain variable region of antibody AL2p-h50,AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10,AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18,AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26,AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77,AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42,AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50,AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58,AL2p-59, AL2p-60, AL2p-61, or AL2p-62 (as shown in Table 7A). In someembodiments that may be combined with any of the preceding embodiments:(a) the HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQ ID NO:132), the HVR-H2 comprises the amino acid sequence RIYPGGGDTNYARKFQG(SEQ ID NO: 133), the HVR-H3 comprises the amino acid sequenceARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1 comprises the amino acidsequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130), the HVR-L2 comprises theamino acid sequence KVSNRRS (SEQ ID NO: 134), and the HVR-L3 comprisesthe amino acid sequence SQSTRVPYT (SEQ ID NO: 129); (b) the HVR-H1comprises the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), the HVR-H2comprises the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135),the HVR-H3 comprises the amino acid sequence ARLLRNQPGESYAMDY (SEQ IDNO: 126), the HVR-L1 comprises the amino acid sequence RSSQSLVHSNGYTYLH(SEQ ID NO: 130), the HVR-L2 comprises the amino acid sequence KVSNRFS(SEQ ID NO: 131), and the HVR-L3 comprises the amino acid sequenceSQSTRVPYT (SEQ ID NO: 129); (c) the HVR-H1 comprises the amino acidsequence YAFSSDWMN (SEQ ID NO: 136), the HVR-H2 comprises the amino acidsequence RIYPGEGDTNYARKFHG (SEQ ID NO: 137), the HVR-H3 comprises theamino acid sequence ARLLRNKPGESYAMDY (SEQ ID NO: 138), the HVR-L1comprises the amino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 139), theHVR-L2 comprises the amino acid sequence KVSNRVS (SEQ ID NO: 140), andthe HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 129);(d) the HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQ ID NO:132), the HVR-H2 comprises the amino acid sequence RIYPGEGDTNYARKFQG(SEQ ID NO: 141), the HVR-H3 comprises the amino acid sequenceARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1 comprises the amino acidsequence RSSQSLVHSNQYTYLH (SEQ ID NO: 142), the HVR-L2 comprises theamino acid sequence KVSNRRS (SEQ ID NO: 134), and the HVR-L3 comprisesthe amino acid sequence SQSTRVPYT (SEQ ID NO: 129); (e) the HVR-H1comprises the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), the HVR-H2comprises the amino acid sequence RIYPGEGDTNYAGKFQG (SEQ ID NO: 143),the HVR-H3 comprises the amino acid sequence ARLLRNQPGESYAMDY (SEQ IDNO: 126), the HVR-L1 comprises the amino acid sequence RSSQSLVHSNQYTYLH(SEQ ID NO: 142), the HVR-L2 comprises the amino acid sequence KVSNRFS(SEQ ID NO: 131), and the HVR-L3 comprises the amino acid sequenceSQSTRVPYT (SEQ ID NO: 129); (f) the HVR-H1 comprises the amino acidsequence YAFSSQWMN (SEQ ID NO: 132), the HVR-H2 comprises the amino acidsequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135), the HVR-H3 comprises theamino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1comprises the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144), theHVR-L2 comprises the amino acid sequence KVSNRFS (SEQ ID NO: 131), andthe HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 129);or (g) the HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQ IDNO: 132), the HVR-H2 comprises the amino acid sequence RIYPGGGDTNYARKFQG(SEQ ID NO: 133), the HVR-H3 comprises the amino acid sequenceARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1 comprises the amino acidsequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144), the HVR-L2 comprises theamino acid sequence KVSNRRS (SEQ ID NO: 134), and the HVR-L3 comprisesthe amino acid sequence SQSTRVPYT (SEQ ID NO: 129). In some embodimentsthat may be combined with any of the preceding embodiments, the HVR-H1comprises the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), the HVR-H2comprises the amino acid sequence RIYPGGGDTNYARKFQG (SEQ ID NO: 133),the HVR-H3 comprises the amino acid sequence ARLLRNQPGESYAMDY (SEQ IDNO: 126), the HVR-L1 comprises the amino acid sequence RSSQSLVHSNGYTYLH(SEQ ID NO: 130), the HVR-L2 comprises the amino acid sequence KVSNRRS(SEQ ID NO: 134), and the HVR-L3 comprises the amino acid sequenceSQSTRVPYT (SEQ ID NO: 129). In some embodiments that may be combinedwith any of the preceding embodiments, the HVR-H1 comprises the aminoacid sequence YAFSSQWMN (SEQ ID NO: 132), the HVR-H2 comprises the aminoacid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135), the HVR-H3 comprisesthe amino acid sequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1comprises the amino acid sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130), theHVR-L2 comprises the amino acid sequence KVSNRFS (SEQ ID NO: 131), andthe HVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 129).In some embodiments that may be combined with any of the precedingembodiments, the HVR-H1 comprises the amino acid sequence YAFSSDWMN (SEQID NO: 136), the HVR-H2 comprises the amino acid sequenceRIYPGEGDTNYARKFHG (SEQ ID NO: 137), the HVR-H3 comprises the amino acidsequence ARLLRNKPGESYAMDY (SEQ ID NO: 138), the HVR-L1 comprises theamino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 139), the HVR-L2comprises the amino acid sequence KVSNRVS (SEQ ID NO: 140), and theHVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 129). Insome embodiments that may be combined with any of the precedingembodiments, the HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQID NO: 132), the HVR-H2 comprises the amino acid sequenceRIYPGEGDTNYARKFQG (SEQ ID NO: 141), the HVR-H3 comprises the amino acidsequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1 comprises theamino acid sequence RSSQSLVHSNQYTYLH (SEQ ID NO: 142), the HVR-L2comprises the amino acid sequence KVSNRRS (SEQ ID NO: 134), and theHVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 129). Insome embodiments that may be combined with any of the precedingembodiments, the HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQID NO: 132), the HVR-H2 comprises the amino acid sequenceRIYPGEGDTNYAGKFQG (SEQ ID NO: 143), the HVR-H3 comprises the amino acidsequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1 comprises theamino acid sequence RSSQSLVHSNQYTYLH (SEQ ID NO: 142), the HVR-L2comprises the amino acid sequence KVSNRFS (SEQ ID NO: 131), and theHVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 129). Insome embodiments that may be combined with any of the precedingembodiments, the HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQID NO: 132), the HVR-H2 comprises the amino acid sequenceRIYPGGGDTNYAGKFQG (SEQ ID NO: 135), the HVR-H3 comprises the amino acidsequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1 comprises theamino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144), the HVR-L2comprises the amino acid sequence KVSNRFS (SEQ ID NO: 131), and theHVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 129). Insome embodiments that may be combined with any of the precedingembodiments, the HVR-H1 comprises the amino acid sequence YAFSSQWMN (SEQID NO: 132), the HVR-H2 comprises the amino acid sequenceRIYPGGGDTNYARKFQG (SEQ ID NO: 133), the HVR-H3 comprises the amino acidsequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1 comprises theamino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144), the HVR-L2comprises the amino acid sequence KVSNRRS (SEQ ID NO: 134), and theHVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 129). Insome embodiments, the HVR-H1 comprises the amino acid sequence YAFSSQWMN(SEQ ID NO: 132), the HVR-H2 comprises the amino acid sequenceRIYPGGGDTNYAGKFQG (SEQ ID NO: 135), the HVR-H3 comprises the amino acidsequence ARLLRNQPGESYAMDY (SEQ ID NO: 126), the HVR-L1 comprises theamino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144), the HVR-L2comprises the amino acid sequence KVSNRFS (SEQ ID NO: 131), and theHVR-L3 comprises the amino acid sequence SQSTRVPYT (SEQ ID NO: 129).

Other aspects of the present disclosure relate to an antibody that bindsto a TREM2 protein, wherein the antibody comprises a heavy chainvariable region and a light chain variable region, wherein the heavychain variable region comprises Kabat CDRs; and/or the light chainvariable region comprises Kabat CDRs. In some embodiments, the heavychain variable region comprises a CDR-H1 comprising the sequence ofSQWMN (SEQ ID NO: 194), a CDR-H2 comprising the sequence ofRIYPGGGDTNYAGKFQG (SEQ ID NO: 135); and a CDR-H3 comprising the sequenceof LLRNQPGESYAMDY (SEQ ID NO: 195). In some embodiments, the light chainvariable region comprises a CDR-L1 comprising the sequence ofRSSQSLVHSNGYTYLH (SEQ ID NO: 130), a CDR-L2 comprising the sequence ofKVSNRFS (SEQ ID NO: 131); and a CDR-L3 comprising the sequence ofSQSTRVPYT (SEQ ID NO: 129). In some embodiments, the heavy chainvariable region comprises a CDR-H1 comprising the sequence of SQWMN (SEQID NO: 194), a CDR-H2 comprising the sequence of RIYPGGGDTNYAGKFQG (SEQID NO: 135); and a CDR-H3 comprising the sequence of LLRNQPGESYAMDY (SEQID NO: 195); and the light chain variable region comprises a CDR-L1comprising the sequence of RSSQSLVHSNGYTYLH (SEQ ID NO: 130), a CDR-L2comprising the sequence of KVSNRFS (SEQ ID NO: 131); and a CDR-L3comprising the sequence of SQSTRVPYT (SEQ ID NO: 129).

Other aspects of the present disclosure relate to an antibody that bindsto a TREM2 protein, wherein the antibody comprises a heavy chainvariable region and a light chain variable region, wherein the heavychain variable region comprises Kabat CDRs; and/or the light chainvariable region comprises Kabat CDRs. In some embodiments, the heavychain variable region comprises a CDR-H1 comprising the sequence ofSDWMN (SEQ ID NO: 196), a CDR-H2 comprising the sequence ofRIYPGEGDTNYARKFHG (SEQ ID NO: 137); and a CDR-H3 comprising the sequenceof LLRNKPGESYAMDY (SEQ ID NO: 197). In some embodiments, the light chainvariable region comprises a CDR-L1 comprising the sequence ofRTSQSLVHSNAYTYLH (SEQ ID NO: 139), a CDR-L2 comprising the sequence ofKVSNRVS (SEQ ID NO: 140); and a CDR-L3 comprising the sequence ofSQSTRVPYT (SEQ ID NO: 129). In some embodiments, the heavy chainvariable region comprises a CDR-H1 comprising the sequence of SDWMN (SEQID NO: 196), a CDR-H2 comprising the sequence of RIYPGEGDTNYARKFHG (SEQID NO: 137); and a CDR-H3 comprising the sequence of LLRNKPGESYAMDY (SEQID NO: 197); and the light chain variable region comprises a CDR-L1comprising the sequence of RTSQSLVHSNAYTYLH (SEQ ID NO: 139), a CDR-L2comprising the sequence of KVSNRVS (SEQ ID NO: 140); and a CDR-L3comprising the sequence of SQSTRVPYT (SEQ ID NO: 129).

Other aspects of the present disclosure relate to an antibody that bindsto a TREM2 protein, wherein the antibody comprises a heavy chainvariable region and a light chain variable region, wherein the heavychain variable region comprises Kabat CDRs; and/or the light chainvariable region comprises Kabat CDRs. In some embodiments, the heavychain variable region comprises a CDR-H1 comprising the sequence ofSQWMN (SEQ ID NO: 194), a CDR-H2 comprising the sequence ofRIYPGGGDTNYAGKFQG (SEQ ID NO: 135); and a CDR-H3 comprising the sequenceof LLRNQPGESYAMDY (SEQ ID NO: 195). In some embodiments, the light chainvariable region comprises a CDR-L1 comprising the sequence ofRSSQSLVHSNRYTYLH (SEQ ID NO: 144), a CDR-L2 comprising the sequence ofKVSNRFS (SEQ ID NO: 131); and a CDR-L3 comprising the sequence ofSQSTRVPYT (SEQ ID NO: 129). In some embodiments, the heavy chainvariable region comprises a CDR-H1 comprising the sequence of SQWMN (SEQID NO: 194), a CDR-H2 comprising the sequence of RIYPGGGDTNYAGKFQG (SEQID NO: 135); and a Kabat CDR-H3 comprising the sequence ofLLRNQPGESYAMDY (SEQ ID NO: 195); and the light chain variable regioncomprises a CDR-L1 comprising the sequence of RSSQSLVHSNRYTYLH (SEQ IDNO: 144), a CDR-L2 comprising the sequence of KVSNRFS (SEQ ID NO: 131);and a CDR-L3 comprising the sequence of SQSTRVPYT (SEQ ID NO: 129).

Other aspects of the present disclosure relate to an antibody that bindsto a TREM2 protein, wherein the antibody comprises a heavy chainvariable region and a light chain variable region, wherein the heavychain variable region comprises Kabat CDRs; and/or the light chainvariable region comprises Kabat CDRs. In some embodiments, the heavychain variable region comprises a CDR-H1 comprising the sequence ofSQWMN (SEQ ID NO: 194), a CDR-H2 comprising the sequence ofRIYPGGGDTNYARKFQG (SEQ ID NO: 133); and a CDR-H3 comprising the sequenceof LLRNQPGESYAMDY (SEQ ID NO: 195). In some embodiments, the light chainvariable region comprises a CDR-L1 comprising the sequence ofRSSQSLVHSNRYTYLH (SEQ ID NO: 144), a CDR-L2 comprising the sequence ofKVSNRRS (SEQ ID NO: 134); and a CDR-L3 comprising the sequence ofSQSTRVPYT (SEQ ID NO: 129). In some embodiments, the heavy chainvariable region comprises a CDR-H1 comprising the sequence of SQWMN (SEQID NO: 194), a CDR-H2 comprising the sequence of RIYPGGGDTNYARKFQG (SEQID NO: 133); and a CDR-H3 comprising the sequence of LLRNQPGESYAMDY (SEQID NO: 195); and the light chain variable region comprises a CDR-L1comprising the sequence of RSSQSLVHSNRYTYLH (SEQ ID NO: 144), a CDR-L2comprising the sequence of KVSNRRS (SEQ ID NO: 134); and a CDR-L3comprising the sequence of SQSTRVPYT (SEQ ID NO: 129).

Other aspects of the present disclosure relate to an antibody that bindsto a TREM2 protein, wherein the antibody comprises a heavy chainvariable region and a light chain variable region, wherein the heavychain variable region comprises Kabat CDRs; and/or the light chainvariable region comprises Kabat CDRs. In some embodiments, the heavychain variable region comprises a CDR-H1 comprising the sequence ofSQWMN (SEQ ID NO: 194), a CDR-H2 comprising the sequence ofRIYPGEGDTNYARKFQG (SEQ ID NO: 141); and a CDR-H3 comprising the sequenceof LLRNQPGESYAMDY (SEQ ID NO: 195). In some embodiments, the light chainvariable region comprises a CDR-L1 comprising the sequence ofRSSQSLVHSNQYTYLH (SEQ ID NO: 142), a CDR-L2 comprising the sequence ofKVSNRRS (SEQ ID NO: 134); and a CDR-L3 comprising the sequence ofSQSTRVPYT (SEQ ID NO: 129). In some embodiments, the heavy chainvariable region comprises a CDR-H1 comprising the sequence of SQWMN (SEQID NO: 194), a CDR-H2 comprising the sequence of RIYPGEGDTNYARKFQG (SEQID NO: 141); and a CDR-H3 comprising the sequence of LLRNQPGESYAMDY (SEQID NO: 195); and the light chain variable region comprises a CDR-L1comprising the sequence of RSSQSLVHSNQYTYLH (SEQ ID NO: 142), a CDR-L2comprising the sequence of KVSNRRS (SEQ ID NO: 134); and a CDR-L3comprising the sequence of SQSTRVPYT (SEQ ID NO: 129).

Other aspects of the present disclosure relate to an antibody that bindsto a TREM2 protein, wherein the antibody comprises a heavy chainvariable region comprising an amino acid sequence selected from thegroup consisting of SEQ ID NOs: 27-71 and 91; and/or a light chainvariable region comprising an amino acid sequence selected from thegroup consisting of SEQ ID NOs: 92-113 and 118. In some embodiments, theantibody comprises the heavy chain variable region of antibody AL2p-h50,AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10,AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18,AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26,AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77,AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42,AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50,AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58,AL2p-59, AL2p-60, AL2p-61, or AL2p-62 (as shown in Table 6A); and/or theantibody comprises the light chain variable region of antibody AL2p-h50,AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10,AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18,AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26,AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77,AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42,AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50,AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58,AL2p-59, AL2p-60, AL2p-61, or AL2p-62 (as shown in Table 7A). In someembodiments: (a) the heavy chain variable region comprises the aminoacid sequence of SEQ ID NO: 53, and/or the light chain variable regioncomprises the amino acid sequence of SEQ ID NO: 97; (b) the heavy chainvariable region comprises the amino acid sequence of SEQ ID NO: 59;and/or the light chain variable region comprises the amino acid sequenceof SEQ ID NO: 104; (c) the heavy chain variable region comprises theamino acid sequence of SEQ ID NO: 64; and/or the light chain variableregion comprises the amino acid sequence of SEQ ID NO: 108; (d) theheavy chain variable region comprises the amino acid sequence of SEQ IDNO: 70; and/or the light chain variable region comprises the amino acidsequence of SEQ ID NO: 110; (e) the heavy chain variable regioncomprises the amino acid sequence of SEQ ID NO: 71; and/or the lightchain variable region comprises the amino acid sequence of SEQ ID NO:111; (f) the heavy chain variable region comprises the amino acidsequence of SEQ ID NO: 59; and/or the light chain variable regioncomprises the amino acid sequence of SEQ ID NO: 112; or (g) the heavychain variable region comprises the amino acid sequence of SEQ ID NO:53; and/or the light chain variable region comprises the amino acidsequence of SEQ ID NO: 113. In some embodiments, the antibody comprisesan Fc region comprising an amino acid sequence selected from the groupconsisting of SEQ ID Nos: 146-156. In some embodiments, the antibodycomprises an Fc region comprising the amino acid sequence of SEQ ID NO:146. In some embodiments, the antibody comprises an Fc region comprisingthe amino acid sequence of SEQ ID NO: 147. In some embodiments, theantibody comprises an Fc region comprising the amino acid sequence ofSEQ ID NO: 148. In some embodiments, the antibody comprises an Fc regioncomprising the amino acid sequence of SEQ ID NO: 149. In someembodiments, the antibody comprises an Fc region comprising the aminoacid sequence of SEQ ID NO: 150. In some embodiments, the antibodycomprises an Fc region comprising the amino acid sequence of SEQ ID NO:151. In some embodiments, the antibody comprises an Fc region comprisingthe amino acid sequence of SEQ ID NO: 152. In some embodiments, theantibody comprises an Fc region comprising the amino acid sequence ofSEQ ID NO: 153. In some embodiments, the antibody comprises an Fc regioncomprising the amino acid sequence of SEQ ID NO: 154. In someembodiments, the antibody comprises an Fc region comprising the aminoacid sequence of SEQ ID NO: 155. In some embodiments, the antibodycomprises an Fc region comprising the amino acid sequence of SEQ ID NO:156. In some embodiments, the antibody comprises a heavy chaincomprising an amino acid sequence selected from the group consisting ofSEQ ID NOs: 198-213; and/or a light chain comprising an amino acidsequence selected from the group consisting of SEQ ID NOs: 214-218. Insome embodiments, the antibody comprises a heavy chain comprising anamino acid sequence selected from the group consisting of SEQ ID NOs:198 and 199; and a light chain comprising the amino acid sequence of SEQID NO: 214. In some embodiments, the antibody comprises a heavy chaincomprising an amino acid sequence selected from the group consisting ofSEQ ID NOs: 200 and 201; and a light chain comprising the amino acidsequence of SEQ ID NO: 214. In some embodiments, the antibody comprisesa heavy chain comprising an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 202 and 203; and a light chain comprising theamino acid sequence of SEQ ID NO: 215. In some embodiments, the antibodycomprises a heavy chain comprising an amino acid sequence selected fromthe group consisting of SEQ ID NOs: 204 and 205; and a light chaincomprising the amino acid sequence of SEQ ID NO: 215. In someembodiments, the antibody comprises a heavy chain comprising an aminoacid sequence selected from the group consisting of SEQ ID NOs: 206 and207; and a light chain comprising the amino acid sequence of SEQ ID NO:216. In some embodiments, the antibody comprises a heavy chaincomprising an amino acid sequence selected from the group consisting ofSEQ ID NOs: 208 and 209; and a light chain comprising the amino acidsequence of SEQ ID NO: 218. In some embodiments, the antibody comprisesa heavy chain comprising an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 210 and 211; and a light chain comprising theamino acid sequence of SEQ ID NO: 218. In some embodiments, the antibodycomprises a heavy chain comprising an amino acid sequence selected fromthe group consisting of SEQ ID NOs: 212 and 213; and a light chaincomprising the amino acid sequence of SEQ ID NO: 217.

In some embodiments, the heavy chain variable region comprises the aminoacid sequence of SEQ ID NO: 53, and/or the light chain variable regioncomprises the amino acid sequence of SEQ ID NO: 97. In some embodiments,the heavy chain variable region comprises the amino acid sequence of SEQID NO: 59; and/or the light chain variable region comprises the aminoacid sequence of SEQ ID NO: 104. In some embodiments, the heavy chainvariable region comprises the amino acid sequence of SEQ ID NO: 64;and/or the light chain variable region comprises the amino acid sequenceof SEQ ID NO: 108. In some embodiments, the heavy chain variable regioncomprises the amino acid sequence of SEQ ID NO: 70; and/or the lightchain variable region comprises the amino acid sequence of SEQ ID NO:110. In some embodiments, the heavy chain variable region comprises theamino acid sequence of SEQ ID NO: 71; and/or the light chain variableregion comprises the amino acid sequence of SEQ ID NO: 11. In someembodiments, the heavy chain variable region comprises the amino acidsequence of SEQ ID NO: 59; and/or the light chain variable regioncomprises the amino acid sequence of SEQ ID NO: 112. In someembodiments, the heavy chain variable region comprises the amino acidsequence of SEQ ID NO: 53; and/or the light chain variable regioncomprises the amino acid sequence of SEQ ID NO: 113.

Other aspects of the present disclosure relate to an antibody that bindsto a TREM2 protein, wherein the antibody comprises a heavy chainvariable region comprising an amino acid sequence selected from thegroup consisting of SEQ ID NOs: 27, 56 and 72-90; and/or a light chainvariable region comprising an amino acid sequence selected from thegroup consisting of SEQ ID NOs: 92, 104, and 114-117. In someembodiments, the antibody comprises the heavy chain variable region ofantibody AL2p-h19, AL2p-h21, AL2p-h22, AL2p-h23, AL2p-h24, AL2p-h25,AL2p-h26, AL2p-h27, AL2p-h28, AL2p-h29, AL2p-h30, AL2p-h31, AL2p-h32,AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36, AL2p-h42, AL2p-h43, AL2p-h44,AL2p-h47, AL2p-h59, AL2p-h76, or AL2p-h90 (as shown in Table 6A); and/orthe antibody comprises the light chain variable region of antibodyAL2p-h19, AL2p-h21, AL2p-h22, AL2p-h23, AL2p-h24, AL2p-h25, AL2p-h26,AL2p-h27, AL2p-h28, AL2p-h29, AL2p-h30, AL2p-h31, AL2p-h32, AL2p-h33,AL2p-h34, AL2p-h35, AL2p-h36, AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47,AL2p-h59, AL2p-h76, or AL2p-h90 (as shown in Table 7A).

Other aspects of the present disclosure relate to an antibody that bindsto a TREM2 protein, wherein the antibody comprises a heavy chaincomprising an amino acid sequence selected from the group consisting ofSEQ ID NOs: 198-213; and/or a light chain comprising an amino acidsequence selected from the group consisting of SEQ ID NOs: 214-218. Insome embodiments, the antibody comprises a heavy chain comprising anamino acid sequence selected from the group consisting of SEQ ID NOs:198 and 199; and a light chain comprising the amino acid sequence of SEQID NO: 214. In some embodiments, the antibody comprises a heavy chaincomprising an amino acid sequence selected from the group consisting ofSEQ ID NOs: 200 and 201; and a light chain comprising the amino acidsequence of SEQ ID NO: 214. In some embodiments, the antibody comprisesa heavy chain comprising an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 202 and 203; and a light chain comprising theamino acid sequence of SEQ ID NO: 215. In some embodiments, the antibodycomprises a heavy chain comprising an amino acid sequence selected fromthe group consisting of SEQ ID NOs: 204 and 205; and a light chaincomprising the amino acid sequence of SEQ ID NO: 215. In someembodiments, the antibody comprises a heavy chain comprising an aminoacid sequence selected from the group consisting of SEQ ID NOs: 206 and207; and a light chain comprising the amino acid sequence of SEQ ID NO:216. In some embodiments, the antibody comprises a heavy chaincomprising an amino acid sequence selected from the group consisting ofSEQ ID NOs: 208 and 209; and a light chain comprising the amino acidsequence of SEQ ID NO: 218. In some embodiments, the antibody comprisesa heavy chain comprising an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 210 and 211; and a light chain comprising theamino acid sequence of SEQ ID NO: 218. In some embodiments, the antibodycomprises a heavy chain comprising an amino acid sequence selected fromthe group consisting of SEQ ID NOs: 212 and 213; and a light chaincomprising the amino acid sequence of SEQ ID NO: 217.

In some embodiments that may be combined with any of the precedingembodiments, the antibody is of the IgG class, the IgM class, or the IgAclass. In some embodiments that may be combined with any of thepreceding embodiments, the antibody is of the IgG class and has an IgG1,IgG2, IgG3, or IgG4 isotype. In some embodiments that may be combinedwith any of the preceding embodiments, the antibody comprises one ormore amino acid substitutions in the Fc region at a residue positionselected from the group consisting of: C127S, L234A, L234F, L235A,L235E, S267E, K322A, L328F, A330S, P331S, E345R, E430G, S440Y, and anycombination thereof, wherein the numbering of the residues is accordingto EU or Kabat numbering. In some embodiments that may be combined withany of the preceding embodiments: (a) the Fc region comprises an aminoacid substitution at positions E430G, L243A, L235A, and P331S, whereinthe numbering of the residue position is according to EU numbering; (b)the Fc region comprises an amino acid substitution at positions E430Gand P331S, wherein the numbering of the residue position is according toEU numbering; (c) the Fc region comprises an amino acid substitution atpositions E430G and K322A, wherein the numbering of the residue positionis according to EU numbering; (d) the Fc region comprises an amino acidsubstitution at positions E430G, A330S, and P331S, wherein the numberingof the residue position is according to EU numbering; (e) the Fc regioncomprises an amino acid substitution at positions E430G, K322A, A330S,and P331S, wherein the numbering of the residue position is according toEU numbering; (f) the Fc region comprises an amino acid substitution atpositions E430G, K322A, and A330S, wherein the numbering of the residueposition is according to EU numbering; (g) the Fc region comprises anamino acid substitution at positions E430G, K322A, and P331S, whereinthe numbering of the residue position is according to EU numbering; (h)the Fc region comprises an amino acid substitution at positions S267Eand L328F, wherein the numbering of the residue position is according toEU numbering; (i) the Fc region comprises an amino acid substitution atposition C127S, wherein the numbering of the residue position isaccording to EU numbering; (j) the Fc region comprises an amino acidsubstitution at positions E345R, E430G and S440Y, wherein the numberingof the residue position is according to EU numbering; or (k) the Fcregion comprises an amino acid sequence selected from the groupconsisting of SEQ ID NOs: 146-156. In some embodiments, the Fc regioncomprises an amino acid substitution at positions E430G and P331S,wherein the numbering of the residue position is according to EUnumbering. In some embodiments, the Fc region comprises an amino acidsubstitution at positions E430G and K322A, wherein the numbering of theresidue position is according to EU numbering. In some embodiments, theFc region comprises an amino acid substitution at positions E430G,A330S, and P331S, wherein the numbering of the residue position isaccording to EU numbering. In some embodiments, the Fc region comprisesthe amino acid sequence of SEQ ID NO: 146. In some embodiments, the Fcregion comprises the amino acid sequence of SEQ ID NO: 147. In someembodiments, the Fc region comprises the amino acid sequence of SEQ IDNO: 148. In some embodiments, the Fc region comprises the amino acidsequence of SEQ ID NO: 149. In some embodiments, the Fc region comprisesthe amino acid sequence of SEQ ID NO: 150. In some embodiments, the Fcregion comprises the amino acid sequence of SEQ ID NO: 151. In someembodiments, the Fc region comprises the amino acid sequence of SEQ IDNO: 152. In some embodiments, the Fc region comprises the amino acidsequence of SEQ ID NO: 153. In some embodiments, the Fc region comprisesthe amino acid sequence of SEQ ID NO: 154. In some embodiments, the Fcregion comprises the amino acid sequence of SEQ ID NO: 155. In someembodiments, the Fc region comprises the amino acid sequence of SEQ IDNO: 156.

In some embodiments that may be combined with any of the precedingembodiments, the TREM2 protein is human protein. In some embodimentsthat may be combined with any of the preceding embodiments, the TREM2protein is a wild-type protein. In some embodiments that may be combinedwith any of the preceding embodiments, the TREM2 protein is a naturallyoccurring variant. In some embodiments that may be combined with any ofthe preceding embodiments, the antibody is an antibody fragment thatbinds to one or more human proteins selected from the group consistingof human TREM2, a naturally occurring variant of human TREM2, and adisease variant of human TREM2, and optionally wherein the antibodyfragment is cross-linked to a second antibody fragment that binds to oneor more human proteins selected from the group consisting of humanTREM2, a naturally occurring variant of human TREM2, and a diseasevariant of human TREM2. In some embodiments that may be combined withany of the preceding embodiments, the fragment is an Fab, Fab′, Fab′-SH,F(ab′)2, Fv or scFv fragment. In some embodiments that may be combinedwith any of the preceding embodiments, the antibody is a monoclonalantibody. In some embodiments that may be combined with any of thepreceding embodiments, the antibody is a humanized antibody.

In some embodiments that may be combined with any of the precedingembodiments, the antibody is a bispecific antibody recognizing a firstantigen and a second antigen, wherein the first antigen is human TREM2or a naturally occurring variant thereof, and the second antigen is: (a)an antigen facilitating transport across the blood-brain-barrier; (b) anantigen facilitating transport across the blood-brain-barrier selectedfrom the group consisting of transferrin receptor (TR), insulin receptor(HIR), insulin-like growth factor receptor (IGFR), low-densitylipoprotein receptor related proteins 1 and 2 (LPR-1 and 2), diphtheriatoxin receptor, CRM197, a llama single domain antibody, TMEM 30(A), aprotein transduction domain, TAT, Syn-B, penetratin, a poly-argininepeptide, an angiopeptide, and ANG1005; (c) a disease-causing agentselected from the group consisting of disease-causing peptides orproteins or, disease-causing nucleic acids, wherein the disease-causingnucleic acids are antisense GGCCCC (G2C4) repeat-expansion RNA, thedisease-causing proteins are selected from the group consisting ofamyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloidprecursor protein or fragments thereof, Tau, IAPP, alpha-synuclein,TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72) c9RANprotein, prion protein, PrPSc, huntingtin, calcitonin, superoxidedismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8,ataxin 10, Lewy body, atrial natriuretic factor, islet amyloidpolypeptide, insulin, apolipoprotein AI, serum amyloid A, medin,prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin,keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein,Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat(DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline(GP) repeat peptides, glycine-arginine (GR) repeat peptides,proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine(PR) repeat peptides; (d) ligands and/or proteins expressed on immunecells, wherein the ligands and/or proteins selected from the groupconsisting of CD40, OX40, ICOS, CD28, CD137/4-1BB, CD27, GITR, PD-L1,CTLA-4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR,LAG-3, and phosphatidylserine; and (e) a protein, lipid, polysaccharide,or glycolipid expressed on one or more tumor cells. In some embodimentsthat may be combined with any of the preceding embodiments, the antibodybinds specifically to both human TREM2 and cynomolgus monkey TREM2. Insome embodiments that may be combined with any of the precedingembodiments, the antibody has a dissociation constant (K_(D)) for humanTREM2 and/or cynomolgus monkey TREM2 that is at least 1-fold lower thanan anti-TREM2 antibody comprising a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO: 27 and a light chainvariable region comprising the amino acid sequence of SEQ ID NO: 56; orat least 1-fold lower than an anti-TREM2 antibody comprising a heavychain variable region comprising the amino acid sequence of SEQ ID NO:91 and a light chain variable region comprising the amino acid sequenceof SEQ ID NO: 103. In some embodiments that may be combined with any ofthe preceding embodiments, the antibody has a dissociation constant(K_(D)) for human TREM2 that ranges from about 9 μM to about 100 pM, orless than 100 pM, wherein the K_(D) is determined at a temperature ofapproximately 25° C. In some embodiments that may be combined with anyof the preceding embodiments, the antibody has a dissociation constant(K_(D)) for cynomolgus monkey TREM2 that ranges from about 50 nM toabout 100 pM, or less than 100 pM, wherein the K_(D) is determined at atemperature of approximately 25° C. In some embodiments that may becombined with any of the preceding embodiments, the antibody binds toprimary human immune cells with an affinity that is at least 10 timeshigher than that of an anti-TREM2 antibody comprising a heavy chainvariable region comprising the amino acid sequence of SEQ ID NO: 27 anda light chain variable region comprising the amino acid sequence of SEQID NO: 56; or at least 10 times higher than an anti-TREM2 antibodycomprising a heavy chain variable region comprising the amino acidsequence of SEQ ID NO: 91 and a light chain variable region comprisingthe amino acid sequence of SEQ ID NO: 103. In some embodiments that maybe combined with any of the preceding embodiments, the antibody clustersand activates TREM2 signaling in an amount that is at least 1-foldgreater than that of an anti-TREM2 antibody comprising a heavy chainvariable region comprising the amino acid sequence of SEQ ID NO: 27 anda light chain variable region comprising the amino acid sequence of SEQID NO: 56; or at least 1-fold greater than an anti-TREM2 antibodycomprising a heavy chain variable region comprising the amino acidsequence of SEQ ID NO: 91 and a light chain variable region comprisingthe amino acid sequence of SEQ ID NO: 103. In some embodiments that maybe combined with any of the preceding embodiments, the antibodyincreases immune cell survival in vitro that to an extent that isgreater than an anti-TREM2 antibody comprising a heavy chain variableregion comprising the amino acid sequence of SEQ ID NO: 27 and a lightchain variable region comprising the amino acid sequence of SEQ ID NO:56; or that is greater than an anti-TREM2 antibody comprising a heavychain variable region comprising the amino acid sequence of SEQ ID NO:91 and a light chain variable region comprising the amino acid sequenceof SEQ ID NO: 103. In some embodiments that may be combined with any ofthe preceding embodiments, the antibody has an in vivo half-life that islower than a human control IgG1 antibody. In some embodiments that maybe combined with any of the preceding embodiments, the antibodydecreases plasma levels of soluble TREM2 in vivo by an amount that is atleast 25% greater than that of a human control IgG1 antibody. In someembodiments that may be combined with any of the preceding embodiments,the antibody decreases plasma levels of soluble TREM2 in vivo byblocking cleavage, by inhibiting one or more metalloproteases, and/or byinducing internalization. In some embodiments, soluble TREM2 isdecreased by about any of 10, 20, 30, 40, or 50%. In some embodimentsthat may be combined with any of the preceding embodiments, the antibodycompetes with one or more antibodies selected from the group consistingof AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8,AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16,AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24,AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32,AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40,AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48,AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56,AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-h19,AL2p-h21, AL2p-h22, AL2p-h23, AL2p-h24, AL2p-h25, AL2p-h26, AL2p-h27,AL2p-h28, AL2p-h29, AL2p-h30, AL2p-h31, AL2p-h32, AL2p-h33, AL2p-h34,AL2p-h35, AL2p-h36, AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47, AL2p-h59,AL2p-h76, AL2p-h90, and any combination thereof for binding to TREM2. Insome embodiments that may be combined with any of the precedingembodiments, the antibody binds essentially the same TREM2 epitope as anantibody selected from the group consisting of: AL2p-h50, AL2p-2,AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10,AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18,AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26,AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77,AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42,AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50,AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58,AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p-h22,AL2p-h23, AL2p-h24, AL2p-h25, AL2p-h26, AL2p-h27, AL2p-h28, AL2p-h29,AL2p-h30, AL2p-h31, AL2p-h32, AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36,AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47, AL2p-h59, AL2p-h76, andAL2p-h90. In some embodiments that may be combined with any of thepreceding embodiments, the antibody binds to one or more amino acidswithin amino acid residues 149-157 of SEQ ID NO: 1. In some embodimentsthat may be combined with any of the preceding embodiments, the antibodybinds to one or more amino acid residues selected from the groupconsisting of E151, D152, and E156 of SEQ ID NO: 1.

Other aspects of the present disclosure relate to an isolated nucleicacid comprising a nucleic acid sequence encoding the antibody of any oneof the preceding embodiments. Other aspects of the present disclosurerelate to a vector comprising the nucleic acid of any one of thepreceding embodiments. Other aspects of the present disclosure relate toan isolated host cell comprising the vector of any one of the precedingembodiments. Other aspects of the present disclosure relate to a methodof producing an antibody that binds to TREM2, comprising culturing thecell of any one of the preceding embodiments so that the antibody isproduced. In some embodiments, the method further comprises recoveringthe antibody produced by the cell. Other aspects of the presentdisclosure relate to an isolated antibody that binds to TREM2 producedby the method of any one of the preceding embodiments. Other aspects ofthe present disclosure relate to a pharmaceutical composition comprisingthe antibody of any one of the preceding embodiments and apharmaceutically acceptable carrier.

Other aspects of the present disclosure relate to a method ofpreventing, reducing risk, or treating an individual having a disease,disorder, or injury selected from the group consisting of dementia,frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease,cognitive deficit, memory loss, spinal cord injury, traumatic braininjury, multiple sclerosis, chronic colitis, ulcerative colitis, andcancer, comprising administering to an individual in need thereof atherapeutically effective amount of the antibody of the precedingembodiments. In some embodiments, the disease, disorder, or injury isAlzheimer's disease.

Other aspects of the present disclosure relate to an antibody comprisingan Fc region, wherein the antibody comprises an amino acid substitutionat position E430G and one or more amino acid substitutions in the Fcregion at a residue position selected from the group consisting of:L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S, and anycombination thereof, wherein the numbering of the residues is accordingto EU or Kabat numbering. In some embodiments: (a) the Fc regioncomprises an amino acid substitution at positions E430G, L243A, L235A,and P331S, wherein the numbering of the residue position is according toEU numbering; (b) the Fc region comprises an amino acid substitution atpositions E430G and P331S, wherein the numbering of the residue positionis according to EU numbering; (c) the Fc region comprises an amino acidsubstitution at positions E430G and K322A, wherein the numbering of theresidue position is according to EU numbering; (d) the Fc regioncomprises an amino acid substitution at positions E430G, A330S, andP331S, wherein the numbering of the residue position is according to EUnumbering; (e) the Fc region comprises an amino acid substitution atpositions E430G, K322A, A330S, and P331S, wherein the numbering of theresidue position is according to EU numbering; (f) the Fc regioncomprises an amino acid substitution at positions E430G, K322A, andA330S, wherein the numbering of the residue position is according to EUnumbering; (g) the Fc region comprises an amino acid substitution atpositions E430G, K322A, and P331S, wherein the numbering of the residueposition is according to EU numbering; of (h) the Fc region comprises anamino acid sequence selected from the group consisting of SEQ ID NOs:146-156. In some embodiments, the Fc region comprises an amino acidsubstitution at positions E430G, L243A, L235A, and P331S, wherein thenumbering of the residue position is according to EU numbering. In someembodiments, the Fc region comprises an amino acid substitution atpositions E430G and P331S, wherein the numbering of the residue positionis according to EU numbering. In some embodiments, the Fc regioncomprises an amino acid substitution at positions E430G and K322A,wherein the numbering of the residue position is according to EUnumbering. In some embodiments, the Fc region comprises an amino acidsubstitution at positions E430G, A330S, and P331S, wherein the numberingof the residue position is according to EU numbering. In someembodiments, the Fc region comprises an amino acid substitution atpositions E430G, K322A, A330S, and P331S, wherein the numbering of theresidue position is according to EU numbering. In some embodiments, theFc region comprises an amino acid substitution at positions E430G,K322A, and A330S, wherein the numbering of the residue position isaccording to EU numbering. In some embodiments, the Fc region comprisesan amino acid substitution at positions E430G, K322A, and P331S, whereinthe numbering of the residue position is according to EU numbering. Insome embodiments, the Fc region increases clustering without activatingcomplement as compared to a corresponding antibody comprising an Fcregion that does not comprise the amino acid substitutions. In someembodiments, the antibody induces one or more activities of a targetspecifically bound by the antibody. In some embodiments, the antibodybinds to TREM2.

It is to be understood that one, some, or all of the properties of thevarious embodiments described herein may be combined to form otherembodiments of the present invention. These and other aspects of theinvention will become apparent to one of skill in the art. These andother embodiments of the invention are further described by the detaileddescription that follows.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A shows increased agonistic activity of Fc variant anti-TREM2antibodies. Luciferase activity after 6 h culture with Fc variants of ananti-TREM2 antibody. FIG. 1B shows increased agonistic activity of Fcvariant anti-TREM2 antibodies. Luciferase activity after 6 hr co-cultureof Fc variant antibodies with BWZ reporter cells and THP-1 cells in 1:1ratio.

FIG. 2A shows C3b deposition induced by Fc variant anti-TREM2antibodies. Fold change of C3b deposition on HEK expressing TREM2 cellline by AL2p Fc variants over human IgG1 isotype control antibody at 10μg/mL. FIG. 2B shows C3b deposition induced by Fc variant anti-TREM2antibodies. Fold change of C3b deposition by AL2p affinity maturedvariants with the listed Fc mutations over their parental IgG1 Fcvariant.

FIG. 3A shows increased activity of soluble anti-TREM2 antibodies. FIG.3B shows increased activity of plate bound anti-TREM2 antibodies. FIG.3C shows reporter activity of affinity matured anti-TREM2 antibodiesplate bound at 5 μg/ml (grey bars) compared to parental humanizedantibody Alp2-h50 (h50), parental humanized antibody AL2p-77 (h77), andparental murine antibody AL2p (AL2p msIgG1 parent) clones (black bars).Clones in grey bars with black outlines represent AL2p-h50 antibodyvariant containing different amino acid substitutions.

FIG. 4A shows increased activity of soluble anti-TREM2 antibodies. FIG.4B shows increased activity of plate bound anti-TREM2 antibodies.

FIG. 5A shows sTREM2 secreted over 48 h by primary human dendritic cellsfrom donor 534 upon incubation with anti-TREM2 or control antibodies.FIG. 5B shows sTREM2 secreted over 48 h by primary human dendritic cellsfrom donor 535 upon incubation with anti-TREM2 or control antibodies.

FIG. 6A shows that there is no change in cell numbers upon incubation ofprimary human dendritic cells of donor 534 with anti-TREM2 or controlantibodies. FIG. 6B shows that there is no change in cell numbers uponincubation of primary human dendritic cells of donor 535 with anti-TREM2or control antibodies.

FIG. 7A shows plasma sTREM2 as % of baseline levels upon singleinjection of 15 mg/kg TREM2 antibodies AL2p-47 huIgG1, AL2p-47 huIgG1ASPSEG, AL2p-58 huIgG1 or control huIgG1. FIG. 7B shows plasma sTREM2 as% of baseline levels upon single injection of 15 mg/kg TREM2 antibodiesAL2p-58 huIgG1, AL2p-58 huIgG1 PSEG or control huIgG1. FIG. 7C showsplasma sTREM2 as % of baseline levels upon single injection of 15 mg/kgTREM2 antibodies AL2p-61 huIgG1 PSEG, AL2p-47 huIgG1, AL2p-58 huIgG1 orcontrol huIgG1. FIG. 7D shows plasma sTREM2 in ng/ml upon singleinjection of 20 mg/kg TREM2 antibodies AL2p msIgG1, T21-9 msIgG1 orcontrol msIgG1.

FIG. 8A and FIG. 8B depict increased viability (as increase in cellularATP) after stimulation of primary human macrophages (FIG. 8A) or humanprimary dendritic cells (FIG. 8B) from one donor with plate bound TREM2antibodies vs. control IgG for 48 hours. FIG. 8C, FIG. 8D, FIG. 8E, andFIG. 8F depict increased viability (as increase in cellular ATP) afterstimulation of primary human dendritic cells of two donors (FIG. 8C andFIG. 8D) or human primary macrophages of two donors (FIG. 8E and FIG.8F) with soluble AL2p-58 huIgG1 vs. control human IgG1 for 48 hours.

FIG. 9 shows Western blot analysis of Dap12 phosphorylation inperitoneal macrophages upon treatment of either WT or TREM2 Bac-Tg micewith AL2p-58 huIgG1, AL2p-58 huIgG1 PSEG or control huIgG1. Cell lysateswere immunoprecipitated with anti-TREM2; upper set of bands showstaining with a phosphotyrosine antibody and lower set show total humanTREM2 levels.

DETAILED DESCRIPTION OF THE PRESENT DISCLOSURE

General Techniques

The techniques and procedures described or referenced herein aregenerally well understood and commonly employed using conventionalmethodology by those skilled in the art, such as, for example, thewidely utilized methodologies described in Sambrook et al., MolecularCloning: A Laboratory Manual 3d edition (2001) Cold Spring HarborLaboratory Press, Cold Spring Harbor, N.Y.; Current Protocols inMolecular Biology (F. M. Ausubel, et al. eds., (2003)); the seriesMethods in Enzymology (Academic Press, Inc.): PCR 2: A PracticalApproach (M. J. MacPherson, B. D. Hames and G. R. Taylor eds. (1995)),Harlow and Lane, eds. (1988) Antibodies, A Laboratory Manual, and AnimalCell Culture (R. I. Freshney, ed. (1987)); Oligonucleotide Synthesis (M.J. Gait, ed., 1984); Methods in Molecular Biology, Humana Press; CellBiology: A Laboratory Notebook (J. E. Cellis, ed., 1998) Academic Press;Animal Cell Culture (R. I. Freshney), ed., 1987); Introduction to Celland Tissue Culture (J. P. Mather and P. E. Roberts, 1998) Plenum Press;Cell and Tissue Culture: Laboratory Procedures (A. Doyle, J. B.Griffiths, and D. G. Newell, eds., 1993-8) J. Wiley and Sons; Handbookof Experimental Immunology (D. M. Weir and C. C. Blackwell, eds.); GeneTransfer Vectors for Mammalian Cells (J. M. Miller and M. P. Calos,eds., 1987); PCR: The Polymerase Chain Reaction, (Mullis et al., eds.,1994); Current Protocols in Immunology (J. E. Coligan et al., eds.,1991); Short Protocols in Molecular Biology (Wiley and Sons, 1999);Immunobiology (C. A. Janeway and P. Travers, 1997); Antibodies (P.Finch, 1997); Antibodies: A Practical Approach (D. Catty, ed., IRLPress, 1988-1989); Monoclonal Antibodies: A Practical Approach (P.Shepherd and C. Dean, eds., Oxford University Press, 2000); UsingAntibodies: A Laboratory Manual (E. Harlow and D. Lane (Cold SpringHarbor Laboratory Press, 1999); The Antibodies (M. Zanetti and J. D.Capra, eds., Harwood Academic Publishers, 1995); and Cancer: Principlesand Practice of Oncology (V. T. DeVita et al., eds., J. B. LippincottCompany, 1993).

Definitions

As used herein, the term “preventing” includes providing prophylaxiswith respect to occurrence or recurrence of a particular disease,disorder, or condition in an individual. An individual may bepredisposed to, susceptible to a particular disease, disorder, orcondition, or at risk of developing such a disease, disorder, orcondition, but has not yet been diagnosed with the disease, disorder, orcondition.

As used herein, an individual “at risk” of developing a particulardisease, disorder, or condition may or may not have detectable diseaseor symptoms of disease, and may or may not have displayed detectabledisease or symptoms of disease prior to the treatment methods describedherein. “At risk” denotes that an individual has one or more riskfactors, which are measurable parameters that correlate with developmentof a particular disease, disorder, or condition, as known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing a particular disease, disorder, or conditionthan an individual without one or more of these risk factors.

As used herein, the term “treatment” refers to clinical interventiondesigned to alter the natural course of the individual being treatedduring the course of clinical pathology. Desirable effects of treatmentinclude decreasing the rate of progression, ameliorating or palliatingthe pathological state, and remission or improved prognosis of aparticular disease, disorder, or condition. An individual issuccessfully “treated”, for example, if one or more symptoms associatedwith a particular disease, disorder, or condition are mitigated oreliminated.

An “effective amount” refers to at least an amount effective, at dosagesand for periods of time necessary, to achieve the desired therapeutic orprophylactic result. An effective amount can be provided in one or moreadministrations. An effective amount herein may vary according tofactors such as the disease state, age, sex, and weight of theindividual, and the ability of the treatment to elicit a desiredresponse in the individual. An effective amount is also one in which anytoxic or detrimental effects of the treatment are outweighed by thetherapeutically beneficial effects. For prophylactic use, beneficial ordesired results include results such as eliminating or reducing therisk, lessening the severity, or delaying the onset of the disease,including biochemical, histological and/or behavioral symptoms of thedisease, its complications and intermediate pathological phenotypespresenting during development of the disease. For therapeutic use,beneficial or desired results include clinical results such asdecreasing one or more symptoms resulting from the disease, increasingthe quality of life of those suffering from the disease, decreasing thedose of other medications required to treat the disease, enhancingeffect of another medication such as via targeting, delaying theprogression of the disease, and/or prolonging survival. An effectiveamount of drug, compound, or pharmaceutical composition is an amountsufficient to accomplish prophylactic or therapeutic treatment eitherdirectly or indirectly. As is understood in the clinical context, aneffective amount of a drug, compound, or pharmaceutical composition mayor may not be achieved in conjunction with another drug, compound, orpharmaceutical composition. Thus, an “effective amount” may beconsidered in the context of administering one or more therapeuticagents, and a single agent may be considered to be given in an effectiveamount if, in conjunction with one or more other agents, a desirableresult may be or is achieved.

An “individual” for purposes of treatment, prevention, or reduction ofrisk refers to any animal classified as a mammal, including humans,domestic and farm animals, and zoo, sport, or pet animals, such as dogs,horses, rabbits, cattle, pigs, hamsters, gerbils, mice, ferrets, rats,cats, and the like. In some embodiments, the individual is human.

As used herein, administration “in conjunction” with another compound orcomposition includes simultaneous administration and/or administrationat different times. Administration in conjunction also encompassesadministration as a co-formulation or administration as separatecompositions, including at different dosing frequencies or intervals,and using the same route of administration or different routes ofadministration.

The term “immunoglobulin” (Ig) is used interchangeably with “antibody”herein. The term “antibody” herein is used in the broadest sense andspecifically covers monoclonal antibodies, polyclonal antibodies,multispecific antibodies (e.g., bispecific antibodies) formed from atleast two intact antibodies, and antibody fragments so long as theyexhibit the desired biological activity.

The basic 4-chain antibody unit is a heterotetrameric glycoproteincomposed of two identical light (L) chains and two identical heavy (H)chains. The pairing of a V_(H) and V_(L) together forms a singleantigen-binding site. For the structure and properties of the differentclasses of antibodies, see, e.g., Basic and Clinical Immunology, 8thEd., Daniel P. Stites, Abba I. Terr and Tristram G. Parslow (eds.),Appleton & Lange, Norwalk, Conn., 1994, page 71 and Chapter 6.

The L chain from any vertebrate species can be assigned to one of twoclearly distinct types, called kappa (“K”) and lambda (“λ”), based onthe amino acid sequences of their constant domains. Depending on theamino acid sequence of the constant domain of their heavy chains (CH),immunoglobulins can be assigned to different classes or isotypes. Thereare five classes of immunoglobulins: IgA, IgD, IgE, IgG, and IgM, havingheavy chains designated alpha (“α”), delta (“δ”), epsilon (“ε”), gamma(“γ”) and mu (“μ”), respectively. The γ and α classes are furtherdivided into subclasses (isotypes) on the basis of relatively minordifferences in the CH sequence and function, e.g., humans express thefollowing subclasses: IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. Thesubunit structures and three dimensional configurations of differentclasses of immunoglobulins are well known and described generally in,for example, Abbas et al., Cellular and Molecular Immunology, 4^(th) ed.(W.B. Saunders Co., 2000).

“Native antibodies” are usually heterotetrameric glycoproteins of about150,000 daltons, composed of two identical light (L) chains and twoidentical heavy (H) chains. Each light chain is linked to a heavy chainby one covalent disulfide bond, while the number of disulfide linkagesvaries among the heavy chains of different immunoglobulin isotypes. Eachheavy and light chain also has regularly spaced intra-chain disulfidebridges. Each heavy chain has at one end a variable domain (V_(H))followed by a number of constant domains. Each light chain has avariable domain at one end (V_(L)) and a constant domain at its otherend; the constant domain of the light chain is aligned with the firstconstant domain of the heavy chain, and the light chain variable domainis aligned with the variable domain of the heavy chain. Particular aminoacid residues are believed to form an interface between the light chainand heavy chain variable domains.

An “isolated” antibody, such as an isolated anti-TREM2 antibody of thepresent disclosure, is one that has been identified, separated and/orrecovered from a component of its production environment (e.g.,naturally or recombinantly). Preferably, the isolated polypeptide isfree of association with all other contaminant components from itsproduction environment. Contaminant components from its productionenvironment, such as those resulting from recombinant transfected cells,are materials that would typically interfere with research, diagnosticor therapeutic uses for the antibody, and may include enzymes, hormones,and other proteinaceous or non-proteinaceous solutes. In preferredembodiments, the polypeptide will be purified: (1) to greater than 95%by weight of antibody as determined by, for example, the Lowry method,and in some embodiments, to greater than 99% by weight; (2) to a degreesufficient to obtain at least 15 residues of N-terminal or internalamino acid sequence by use of a spinning cup sequenator, or (3) tohomogeneity by SDS-PAGE under non-reducing or reducing conditions usingCoomassie blue or, preferably, silver stain. Isolated antibody includesthe antibody in situ within recombinant T-cells since at least onecomponent of the antibody's natural environment will not be present.Ordinarily, however, an isolated polypeptide or antibody will beprepared by at least one purification step.

The “variable region” or “variable domain” of an antibody, such as ananti-TREM2 antibody of the present disclosure, refers to theamino-terminal domains of the heavy or light chain of the antibody. Thevariable domains of the heavy chain and light chain may be referred toas “V_(H)” and “V_(L)”, respectively. These domains are generally themost variable parts of the antibody (relative to other antibodies of thesame class) and contain the antigen binding sites.

The term “variable” refers to the fact that certain segments of thevariable domains differ extensively in sequence among antibodies, suchas anti-TREM2 antibodies of the present disclosure. The V domainmediates antigen binding and defines the specificity of a particularantibody for its particular antigen. However, the variability is notevenly distributed across the entire span of the variable domains.Instead, it is concentrated in three segments called hypervariableregions (HVRs) both in the light-chain and the heavy chain variabledomains. The more highly conserved portions of variable domains arecalled the framework regions (FR). The variable domains of native heavyand light chains each comprise four FR regions, largely adopting abeta-sheet configuration, connected by three HVRs, which form loopsconnecting, and in some cases forming part of, the beta-sheet structure.The HVRs in each chain are held together in close proximity by the FRregions and, with the HVRs from the other chain, contribute to theformation of the antigen-binding site of antibodies (see Kabat et al.,Sequences of Immunological Interest, Fifth Edition, National Instituteof Health, Bethesda, Md. (1991)). The constant domains are not involveddirectly in the binding of antibody to an antigen, but exhibit variouseffector functions, such as participation of the antibody inantibody-dependent-cellular toxicity.

The term “monoclonal antibody” as used herein refers to an antibody,such as a monoclonal anti-TREM2 antibody of the present disclosure,obtained from a population of substantially homogeneous antibodies,i.e., the individual antibodies comprising the population are identicalexcept for possible naturally occurring mutations and/orpost-translation modifications (e.g., isomerizations, amidations, etc.)that may be present in minor amounts. Monoclonal antibodies are highlyspecific, being directed against a single antigenic site. In contrast topolyclonal antibody preparations which typically include differentantibodies directed against different determinants (epitopes), eachmonoclonal antibody is directed against a single determinant on theantigen. In addition to their specificity, the monoclonal antibodies areadvantageous in that they are synthesized by the hybridoma culture,uncontaminated by other immunoglobulins. The modifier “monoclonal”indicates the character of the antibody as being obtained from asubstantially homogeneous population of antibodies, and is not to beconstrued as requiring production of the antibody by any particularmethod. For example, the monoclonal antibodies to be used in accordancewith the present invention may be made by a variety of techniques,including, for example, the hybridoma method (e.g., Kohler and Milstein,Nature, 256:495-97 (1975); Hongo et al., Hybridoma, 14 (3):253-260(1995), Harlow et al., Antibodies: A Laboratory Manual, (Cold SpringHarbor Laboratory Press, 2d ed. 1988); Hammerling et al., in: MonoclonalAntibodies and T-Cell Hybridomas 563-681 (Elsevier, N.Y., 1981)),recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567),phage-display technologies (see, e.g., Clackson et al., Nature,352:624-628 (1991); Marks et al., J. Mol. Biol. 222:581-597 (1992);Sidhu et al., J. Mol. Biol. 338(2): 299-310 (2004); Lee et al., J. Mol.Biol. 340(5):1073-1093 (2004); Fellouse, Proc. Nat'l Acad. Sci. USA101(34):12467-472 (2004); and Lee et al., J. Immunol. Methods 284(1-2):119-132 (2004), yeast presentation technologies (see, e.g.,WO2009/036379A2; WO2010105256; WO2012009568, and Xu et al., Protein Eng.Des. Sel., 26(10): 663-70 (2013), and technologies for producing humanor human-like antibodies in animals that have parts or all of the humanimmunoglobulin loci or genes encoding human immunoglobulin sequences(see, e.g., WO 1998/24893; WO 1996/34096; WO 1996/33735; WO 1991/10741;Jakobovits et al., Proc. Nat'l Acad Sci. USA 90:2551 (1993); Jakobovitset al., Nature 362:255-258 (1993); Bruggemann et al., Year in Immunol.7:33 (1993); U.S. Pat. Nos. 5,545,807; 5,545,806; 5,569,825; 5,625,126;5,633,425; and 5,661,016; Marks et al., Bio/Technology 10:779-783(1992); Lonberg et al., Nature 368:856-859 (1994); Morrison, Nature368:812-813 (1994); Fishwild et al., Nature Biotechnol. 14:845-851(1996); Neuberger, Nature Biotechnol. 14:826 (1996); and Lonberg andHuszar, Intern. Rev. Immunol. 13:65-93 (1995).

The terms “full-length antibody,” “intact antibody” or “whole antibody”are used interchangeably to refer to an antibody, such as an anti-TREM2antibody of the present disclosure, in its substantially intact form, asopposed to an antibody fragment. Specifically whole antibodies includethose with heavy and light chains including an Fc region. The constantdomains may be native sequence constant domains (e.g., human nativesequence constant domains) or amino acid sequence variants thereof. Insome cases, the intact antibody may have one or more effector functions.

An “antibody fragment” comprises a portion of an intact antibody,preferably the antigen binding and/or the variable region of the intactantibody. Examples of antibody fragments include Fab, Fab′, F(ab′)₂ andFv fragments; diabodies; linear antibodies (see U.S. Pat. No. 5,641,870,Example 2; Zapata et al., Protein Eng. 8(10):1057-1062 (1995));single-chain antibody molecules and multispecific antibodies formed fromantibody fragments.

Papain digestion of antibodies, such as anti-TREM2 antibodies of thepresent disclosure, produces two identical antigen-binding fragments,called “Fab” fragments, and a residual “Fc” fragment, a designationreflecting the ability to crystallize readily. The Fab fragment consistsof an entire L chain along with the variable region domain of the Hchain (V_(H)), and the first constant domain of one heavy chain(C_(H)1). Each Fab fragment is monovalent with respect to antigenbinding, i.e., it has a single antigen-binding site. Pepsin treatment ofan antibody yields a single large F(ab′)₂ fragment which roughlycorresponds to two disulfide linked Fab fragments having differentantigen-binding activity and is still capable of cross-linking antigen.Fab′ fragments differ from Fab fragments by having a few additionalresidues at the carboxy terminus of the C_(H)1 domain including one ormore cysteines from the antibody hinge region. Fab′-SH is thedesignation herein for Fab′ in which the cysteine residue(s) of theconstant domains bear a free thiol group. F(ab′)₂ antibody fragmentsoriginally were produced as pairs of Fab′ fragments which have hingecysteines between them. Other chemical couplings of antibody fragmentsare also known.

The Fc fragment comprises the carboxy-terminal portions of both H chainsheld together by disulfides. The effector functions of antibodies aredetermined by sequences in the Fc region, the region which is alsorecognized by Fc receptors (FcR) found on certain types of cells.

“Fv” is the minimum antibody fragment which contains a completeantigen-recognition and -binding site. This fragment consists of a dimerof one heavy- and one light-chain variable region domain in tight,non-covalent association. From the folding of these two domains emanatesix hypervariable loops (3 loops each from the H and L chain) thatcontribute the amino acid residues for antigen binding and conferantigen binding specificity to the antibody. However, even a singlevariable domain (or half of an Fv comprising only three HVRs specificfor an antigen) has the ability to recognize and bind antigen, althoughat a lower affinity than the entire binding site.

“Single-chain Fv” also abbreviated as “sFv” or “scFv” are antibodyfragments that comprise the VH and VL antibody domains connected into asingle polypeptide chain. Preferably, the sFv polypeptide furthercomprises a polypeptide linker between the V_(H) and V_(L) domains,which enables the sFv to form the desired structure for antigen binding.For a review of the sFv, see Plückthun in The Pharmacology of MonoclonalAntibodies, vol. 113, Rosenburg and Moore eds., Springer-VerLAG-3, NewYork, pp. 269-315 (1994).

“Functional fragments” of antibodies, such as anti-TREM2 antibodies ofthe present disclosure, comprise a portion of an intact antibody,generally including the antigen binding or variable region of the intactantibody or the F region of an antibody which retains or has modifiedFcR binding capability. Examples of antibody fragments include linearantibody, single-chain antibody molecules and multispecific antibodiesformed from antibody fragments.

The term “diabodies” refers to small antibody fragments prepared byconstructing sFv fragments (see preceding paragraph) with short linkers(about 5-10) residues) between the V_(H) and V_(L) domains such thatinter-chain but not intra-chain pairing of the V domains is achieved,thereby resulting in a bivalent fragment, i.e., a fragment having twoantigen-binding sites. Bispecific diabodies are heterodimers of two“crossover” sFv fragments in which the V_(H) and V_(L) domains of thetwo antibodies are present on different polypeptide chains. Diabodiesare described in greater detail in, for example, EP 404,097; WO93/11161; Hollinger et al., Proc. Nat'l Acad Sci. USA 90:6444-48 (1993).

As used herein, a “chimeric antibody” refers to an antibody(immunoglobulin), such as a chimeric anti-TREM2 antibody of the presentdisclosure, in which a portion of the heavy and/or light chain isidentical with or homologous to corresponding sequences in antibodiesderived from a particular species or belonging to a particular antibodyclass or subclass, while the remainder of the chain(s) is(are) identicalwith or homologous to corresponding sequences in antibodies derived fromanother species or belonging to another antibody class or subclass, aswell as fragments of such antibodies, so long as they exhibit thedesired biological activity (U.S. Pat. No. 4,816,567; Morrison et al.,Proc. Nat'l Acad. Sci. USA, 81:6851-55 (1984)). Chimeric antibodies ofinterest herein include PRIMATIZED® antibodies wherein theantigen-binding region of the antibody is derived from an antibodyproduced by, e.g., immunizing macaque monkeys with an antigen ofinterest. As used herein, “humanized antibody” is used a subsetof“chimeric antibodies.”

“Humanized” forms of non-human (e.g., murine) antibodies, such ashumanized forms of anti-TREM2 antibodies of the present disclosure, arechimeric antibodies that contain minimal sequence derived from non-humanimmunoglobulin. In one embodiment, a humanized antibody is a humanimmunoglobulin (recipient antibody) in which residues from an HVR of therecipient are replaced by residues from an HVR of a non-human species(donor antibody) such as mouse, rat, rabbit or non-human primate havingthe desired specificity, affinity, and/or capacity. In some instances,FR residues of the human immunoglobulin are replaced by correspondingnon-human residues. Furthermore, humanized antibodies may compriseresidues that are not found in the recipient antibody or in the donorantibody. These modifications may be made to further refine antibodyperformance, such as binding affinity. In general, a humanized antibodywill comprise substantially all of at least one, and typically two,variable domains, in which all or substantially all of the hypervariableloops correspond to those of a non-human immunoglobulin sequence, andall or substantially all of the FR regions are those of a humanimmunoglobulin sequence, although the FR regions may include one or moreindividual FR residue substitutions that improve antibody performance,such as binding affinity, isomerization, immunogenicity, and the like.The number of these amino acid substitutions in the FR is typically nomore than 6 in the H chain, and in the L chain, no more than 3. Thehumanized antibody optionally will also comprise at least a portion ofan immunoglobulin constant region (Fc), typically that of a humanimmunoglobulin. For further details, see, e.g., Jones et al., Nature321:522-525 (1986); Riechmann et al., Nature 332:323-329 (1988); andPresta, Curr. Op. Struct. Biol. 2:593-596 (1992). See also, for example,Vaswani and Hamilton, Ann. Allergy, Asthma & Immunol. 1:105-115 (1998);Harris, Biochem. Soc. Transactions 23:1035-1038 (1995); Hurle and Gross,Curr. Op. Biotech. 5:428-433 (1994); and U.S. Pat. Nos. 6,982,321 and7,087,409.

A “human antibody” is one that possesses an amino-acid sequencecorresponding to that of an antibody, such as an anti-TREM2 antibody ofthe present disclosure, produced by a human and/or has been made usingany of the techniques for making human antibodies as disclosed herein.This definition of a human antibody specifically excludes a humanizedantibody comprising non-human antigen-binding residues. Human antibodiescan be produced using various techniques known in the art, includingphage-display libraries. Hoogenboom and Winter, J. Mol. Biol., 227:381(1991); Marks et al., J. Mol. Biol., 222:581 (1991). Also available forthe preparation of human monoclonal antibodies are methods described inCole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p.77 (1985); Boerner et al., J. Immunol., 147(1):86-95 (1991). See alsovan Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74 (2001).Human antibodies can be prepared by administering the antigen to atransgenic animal that has been modified to produce such antibodies inresponse to antigenic challenge, but whose endogenous loci have beendisabled, e.g., immunized xenomice (see, e.g., U.S. Pat. Nos. 6,075,181and 6,150,584 regarding XENOMOUSE™ technology). See also, for example,Li et al., Proc. Nat'l Acad Sci. USA, 103:3557-3562 (2006) regardinghuman antibodies generated via a human B-cell hybridoma technology.Alternatively, human antibodies can also be prepared by employing yeastlibraries and methods as disclosed in, for example, WO2009/036379A2;WO2010105256; WO2012009568; and Xu et al., Protein Eng. Des. Sel.,26(10): 663-70 (2013).

The term “hypervariable region,” “HVR,” or “HV,” when used herein refersto the regions of an antibody-variable domain, such as that of ananti-TREM2 antibody of the present disclosure, that are hypervariable insequence and/or form structurally defined loops. Generally, antibodiescomprise six HVRs; three in the VH (H1, H2, H3), and three in the VL(L1, L2, L3). In native antibodies, H3 and L3 display the most diversityof the six HVRs, and H3 in particular is believed to play a unique rolein conferring fine specificity to antibodies. See, e.g., Xu et al.,Immunity 13:37-45 (2000); Johnson and Wu in Methods in Molecular Biology248:1-25 (Lo, ed., Human Press, Totowa, N.J., 2003)). Indeed, naturallyoccurring camelid antibodies consisting of a heavy chain only arefunctional and stable in the absence of light chain. See, e.g.,Hamers-Casterman et al., Nature 363:446-448 (1993) and Sheriff et al.,Nature Struct. Biol. 3:733-736 (1996).

A number of HVR delineations are in use and are encompassed herein. Insome embodiments, the HVRs may be Kabat complementarity-determiningregions (CDRs) based on sequence variability and are the most commonlyused (Kabat et al., supra). In some embodiments, the HVRs may be ChothiaCDRs. Chothia refers instead to the location of the structural loops(Chothia and Lesk J. Mol. Biol. 196:901-917 (1987)). In someembodiments, the HVRs may be AbM HVRs. The AbM HVRs represent acompromise between the Kabat CDRs and Chothia structural loops, and areused by Oxford Molecular's AbM antibody-modeling software. In someembodiments, the HVRs may be “contact” HVRs. The “contact” HVRs arebased on an analysis of the available complex crystal structures. Theresidues from each of these HVRs are noted below.

Loop Kabat AbM Chothia Contact L1 L24-L34 L24-L34 L26-L32 L30-L36 L2L50-L56 L50-L56 L50-L52 L46-L55 L3 L89-L97 L89-L97 L91-L96 L89-L96 H1H31-H35B H26-H35B H26-H32 H30-H35B (Kabat numbering) H1 H31-H35 H26-H35H26-H32 H30-H35 (Chothia numbering) H2 H50-H65 H50-H58 H53-H55 H47-H58H3 H95-H102 H95-H102 H96-H101 H93-H101

HVRs may comprise “extended HVRs” as follows: 24-36 or 24-34 (L1), 46-56or 50-56 (L2), and 89-97 or 89-96 (L3) in the VL, and 26-35 (H1), 50-65or 49-65 (a preferred embodiment) (H2), and 93-102, 94-102, or 95-102(H3) in the VH. The variable-domain residues are numbered according toKabat et al., supra, for each of these extended-HVR definitions.

“Framework” or “FR” residues are those variable-domain residues otherthan the HVR residues as herein defined.

The phrase “variable-domain residue-numbering as in Kabat” or“amino-acid-position numbering as in Kabat,” and variations thereof,refers to the numbering system used for heavy-chain variable domains orlight-chain variable domains of the compilation of antibodies in Kabatet al., supra. Using this numbering system, the actual linear amino acidsequence may contain fewer or additional amino acids corresponding to ashortening of, or insertion into, a FR or HVR of the variable domain.For example, a heavy-chain variable domain may include a single aminoacid insert (residue 52a according to Kabat) after residue 52 of H2 andinserted residues (e.g., residues 82a, 82b, and 82c, etc. according toKabat) after heavy-chain FR residue 82. The Kabat numbering of residuesmay be determined for a given antibody by alignment at regions ofhomology of the sequence of the antibody with a “standard” Kabatnumbered sequence.

The Kabat numbering system is generally used when referring to a residuein the variable domain (approximately residues 1-107 of the light chainand residues 1-113 of the heavy chain) (e.g., Kabat et al., Sequences ofImmunological Interest. 5th Ed. Public Health Service, NationalInstitutes of Health, Bethesda, Md. (1991)). The “EU or, Kabat numberingsystem” or “EU index” is generally used when referring to a residue inan immunoglobulin heavy chain constant region (e.g., the EU indexreported in Kabat et al., supra). The “EU index as in Kabat” refers tothe residue numbering of the human IgG1 EU antibody. References toresidue numbers in the variable domain of antibodies means residuenumbering by the Kabat numbering system. References to residue numbersin the constant domain of antibodies means residue numbering by the EUor, Kabat numbering system (e.g., see United States Patent PublicationNo. 2010-280227).

An “acceptor human framework” as used herein is a framework comprisingthe amino acid sequence of a VL or VH framework derived from a humanimmunoglobulin framework or a human consensus framework. An acceptorhuman framework “derived from” a human immunoglobulin framework or ahuman consensus framework may comprise the same amino acid sequencethereof, or it may contain pre-existing amino acid sequence changes. Insome embodiments, the number of pre-existing amino acid changes are 10or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 orless, 3 or less, or 2 or less. Where pre-existing amino acid changes arepresent in a VH, preferable those changes occur at only three, two, orone of positions 71H, 73H and 78H; for instance, the amino acid residuesat those positions may by 71A, 73T and/or 78A. In one embodiment, the VLacceptor human framework is identical in sequence to the VL humanimmunoglobulin framework sequence or human consensus framework sequence.

A “human consensus framework” is a framework that represents the mostcommonly occurring amino acid residues in a selection of humanimmunoglobulin VL or VH framework sequences. Generally, the selection ofhuman immunoglobulin VL or VH sequences is from a subgroup of variabledomain sequences. Generally, the subgroup of sequences is a subgroup asin Kabat et al., Sequences of Proteins of Immunological Interest, 5thEd. Public Health Service, National Institutes of Health, Bethesda, Md.(1991). Examples include for the VL, the subgroup may be subgroup kappaI, kappa II, kappa III or kappa IV as in Kabat et al., supra.Additionally, for the VH, the subgroup may be subgroup I, subgroup II,or subgroup III as in Kabat et al., supra.

An “amino-acid modification” at a specified position, e.g., of ananti-TREM2 antibody of the present disclosure, refers to thesubstitution or deletion of the specified residue, or the insertion ofat least one amino acid residue adjacent the specified residue.Insertion “adjacent” to a specified residue means insertion within oneto two residues thereof. The insertion may be N-terminal or C-terminalto the specified residue. The preferred amino acid modification hereinis a substitution.

An “affinity-matured” antibody, such as an affinity matured anti-TREM2antibody of the present disclosure, is one with one or more alterationsin one or more HVRs thereof that result in an improvement in theaffinity of the antibody for antigen, compared to a parent antibody thatdoes not possess those alteration(s). In one embodiment, anaffinity-matured antibody has nanomolar or even picomolar affinities forthe target antigen. Affinity-matured antibodies are produced byprocedures known in the art. For example, Marks et al., Bio/Technology10:779-783 (1992) describes affinity maturation by VH- and VL-domainshuffling. Random mutagenesis of HVR and/or framework residues isdescribed by, for example: Barbas et al. Proc Nat. Acad. Sci. USA91:3809-3813 (1994); Schier et al. Gene 169:147-155 (1995); Yelton etal. J. Immunol. 155:1994-2004 (1995); Jackson et al., J. Immunol.154(7):3310-9 (1995); and Hawkins et al, J. Mol. Biol. 226:889-896(1992).

As use herein, the term “specifically recognizes” or “specificallybinds” refers to measurable and reproducible interactions such asattraction or binding between a target and an antibody, such as betweenan anti-TREM2 antibody and TREM2 that is determinative of the presenceof the target in the presence of a heterogeneous population of moleculesincluding biological molecules. For example, an antibody, such as ananti-TREM2 antibody of the present disclosure, that specifically orpreferentially binds to a target or an epitope is an antibody that bindsthis target or epitope with greater affinity, avidity, more readily,and/or with greater duration than it binds to other targets or otherepitopes of the target. It is also understood by reading this definitionthat, for example, an antibody (or a moiety) that specifically orpreferentially binds to a first target may or may not specifically orpreferentially bind to a second target. As such, “specific binding” or“preferential binding” does not necessarily require (although it caninclude) exclusive binding. An antibody that specifically binds to atarget may have an association constant of at least about 10³ M⁻¹ or 10⁴M⁻¹, sometimes about 10⁵ M⁻¹ or 10⁶ M⁻¹, in other instances about 10⁶M⁻¹ or 10⁷ M⁻¹, about 10 M⁻¹ to 10⁹ M⁻¹, or about 10¹⁰ M⁻¹ to 10¹¹ M⁻¹or higher. A variety of immunoassay formats can be used to selectantibodies specifically immunoreactive with a particular protein. Forexample, solid-phase ELISA immunoassays are routinely used to selectmonoclonal antibodies specifically immunoreactive with a protein. See,e.g., Harlow and Lane (1988) Antibodies, A Laboratory Manual, ColdSpring Harbor Publications, New York, for a description of immunoassayformats and conditions that can be used to determine specificimmunoreactivity.

As used herein, an “interaction” between a TREM2 protein and a secondprotein encompasses, without limitation, protein-protein interaction, aphysical interaction, a chemical interaction, binding, covalent binding,and ionic binding. As used herein, an antibody “inhibits interaction”between two proteins when the antibody disrupts, reduces, or completelyeliminates an interaction between the two proteins. An antibody of thepresent disclosure, or fragment thereof, “inhibits interaction” betweentwo proteins when the antibody or fragment thereof binds to one of thetwo proteins.

An “agonist” antibody or an “activating” antibody is an antibody thatinduces (e.g., increases) one or more activities or functions of theantigen after the antibody binds the antigen.

An “antagonist” antibody or a “blocking” antibody is an antibody thatreduces or eliminates (e.g., decreases) antigen binding to one or moreligand after the antibody binds the antigen, and/or that reduces oreliminates (e.g., decreases) one or more activities or functions of theantigen after the antibody binds the antigen. In some embodiments,antagonist antibodies, or blocking antibodies substantially orcompletely inhibit antigen binding to one or more ligand and/or one ormore activities or functions of the antigen.

Antibody “effector functions” refer to those biological activitiesattributable to the Fc region (a native sequence Fc region or amino acidsequence variant Fc region) of an antibody, and vary with the antibodyisotype.

The term “Fc region” herein is used to define a C-terminal region of animmunoglobulin heavy chain, including native-sequence Fc regions andvariant Fc regions. Although the boundaries of the Fc region of animmunoglobulin heavy chain might vary, the human IgG heavy-chain Fcregion is usually defined to stretch from an amino acid residue atposition Cys226, or from Pro230, to the carboxyl-terminus thereof. TheC-terminal lysine (residue 447 according to the EU or, Kabat numberingsystem) of the Fc region may be removed, for example, during productionor purification of the antibody, or by recombinantly engineering thenucleic acid encoding a heavy chain of the antibody. Accordingly, acomposition of intact antibodies may comprise antibody populations withall K447 residues removed, antibody populations with no K447 residuesremoved, and antibody populations having a mixture of antibodies withand without the K447 residue. Suitable native-sequence Fc regions foruse in the antibodies of the present disclosure include human IgG1,IgG2, IgG3 and IgG4.

A “native sequence Fc region” comprises an amino acid sequence identicalto the amino acid sequence of an Fc region found in nature. Nativesequence human Fc regions include a native sequence human IgG1 Fc region(non-A and A allotypes); native sequence human IgG2 Fc region; nativesequence human IgG3 Fc region; and native sequence human IgG4 Fc regionas well as naturally occurring variants thereof.

A “variant Fc region” comprises an amino acid sequence which differsfrom that of a native sequence Fc region by virtue of at least one aminoacid modification, preferably one or more amino acid substitution(s).Preferably, the variant Fc region has at least one amino acidsubstitution compared to a native sequence Fc region or to the Fc regionof a parent polypeptide, e.g. from about one to about ten amino acidsubstitutions, and preferably from about one to about five amino acidsubstitutions in a native sequence Fc region or in the Fc region of theparent polypeptide. The variant Fc region herein will preferably possessat least about 80% homology with a native sequence Fc region and/or withan Fc region of a parent polypeptide, and most preferably at least about90% homology therewith, more preferably at least about 95% homologytherewith.

“Fc receptor” or “FcR” describes a receptor that binds to the Fc regionof an antibody. The preferred FcR is a native sequence human FcR.Moreover, a preferred FcR is one which binds an IgG antibody (a gammareceptor) and includes receptors of the FcγRI, FcγRII, and FcγRIIIsubclasses, including allelic variants and alternatively spliced formsof these receptors, FcγRII receptors include FcγRIIA (an “activatingreceptor”) and FcγRIIB (an “inhibiting receptor”), which have similaramino acid sequences that differ primarily in the cytoplasmic domainsthereof. Activating receptor FcγRIIA contains an immunoreceptortyrosine-based activation motif (“ITAM”) in its cytoplasmic domain.Inhibiting receptor FcγRIIB contains an immunoreceptor tyrosine-basedinhibition motif (“ITIM”) in its cytoplasmic domain. (see, e.g., M.Daeron, Annu. Rev. Immunol. 15:203-234 (1997)). FcRs are reviewed inRavetch and Kinet, Annu. Rev. Immunol. 9:457-92 (1991); Capel et al.,Immunomethods 4:25-34 (1994); and de Haas et al., J. Lab. Clin. Med.126: 330-41 (1995). Other FcRs, including those to be identified in thefuture, are encompassed by the term “FcR” herein. FcRs can also increasethe serum half-life of antibodies.

Binding to FcRn in vivo and serum half-life of human FcRn high-affinitybinding polypeptides can be assayed, e.g., in transgenic mice ortransfected human cell lines expressing human FcRn, or in primates towhich the polypeptides having a variant Fc region are administered. WO2004/42072 (Presta) describes antibody variants with improved ordiminished binding to FcRs. See also, e.g., Shields et al., J. Biol.Chem. 9(2):6591-6604 (2001).

As used herein, “percent (%) amino acid sequence identity” and“homology” with respect to a peptide, polypeptide or antibody sequencerefers to the percentage of amino acid residues in a candidate sequencethat are identical with the amino acid residues in the specific peptideor polypeptide sequence, after aligning the sequences and introducinggaps, if necessary, to achieve the maximum percent sequence identity,and not considering any conservative substitutions as part of thesequence identity. Alignment for purposes of determining percent aminoacid sequence identity can be achieved in various ways that are withinthe skill in the art, for instance, using publicly available computersoftware such as BLAST, BLAST-2, ALIGN or MEGALIGN™ (DNASTAR) software.Those skilled in the art can determine appropriate parameters formeasuring alignment, including any algorithms known in the art needed toachieve maximal alignment over the full-length of the sequences beingcompared.

An “isolated” nucleic acid molecule encoding an antibody, such as ananti-TREM2 antibody of the present disclosure, is a nucleic acidmolecule that is identified and separated from at least one contaminantnucleic acid molecule with which it is ordinarily associated in theenvironment in which it was produced. Preferably, the isolated nucleicacid is free of association with all components associated with theproduction environment. The isolated nucleic acid molecules encoding thepolypeptides and antibodies herein is in a form other than in the formor setting in which it is found in nature. Isolated nucleic acidmolecules therefore are distinguished from nucleic acid encoding thepolypeptides and antibodies herein existing naturally in cells.

The term “vector,” as used herein, is intended to refer to a nucleicacid molecule capable of transporting another nucleic acid to which ithas been linked. One type of vector is a “plasmid,” which refers to acircular double stranded DNA into which additional DNA segments may beligated. Another type of vector is a phage vector. Another type ofvector is a viral vector, wherein additional DNA segments may be ligatedinto the viral genome. Certain vectors are capable of autonomousreplication in a host cell into which they are introduced (e.g.,bacterial vectors having a bacterial origin of replication and episomalmammalian vectors). Other vectors (e.g., non-episomal mammalian vectors)can be integrated into the genome of a host cell upon introduction intothe host cell, and thereby are replicated along with the host genome.Moreover, certain vectors are capable of directing the expression ofgenes to which they are operatively linked. Such vectors are referred toherein as “recombinant expression vectors,” or simply, “expressionvectors.” In general, expression vectors of utility in recombinant DNAtechniques are often in the form of plasmids. In the presentspecification, “plasmid” and “vector” may be used interchangeably as theplasmid is the most commonly used form of vector.

“Polynucleotide,” or “nucleic acid,” as used interchangeably herein,refer to polymers of nucleotides of any length, and include DNA and RNA.The nucleotides can be deoxyribonucleotides, ribonucleotides, modifiednucleotides or bases, and/or their analogs, or any substrate that can beincorporated into a polymer by DNA or RNA polymerase or by a syntheticreaction. A polynucleotide may comprise modified nucleotides, such asmethylated nucleotides and their analogs. If present, modification tothe nucleotide structure may be imparted before or after assembly of thepolymer. The sequence of nucleotides may be interrupted bynon-nucleotide components. A polynucleotide may comprise modification(s)made after synthesis, such as conjugation to a label. Other types ofmodifications include, for example, “caps,” substitution of one or moreof the naturally occurring nucleotides with an analog, internucleotidemodifications such as, for example, those with uncharged linkages (e.g.,methyl phosphonates, phosphotriesters, phosphoamidates, carbamates,etc.) and with charged linkages (e.g., phosphorothioates,phosphorodithioates, etc.), those containing pendant moieties, such as,for example, proteins (e.g., nucleases, toxins, antibodies, signalpeptides, ply-L-lysine, etc.), those with intercalators (e.g., acridine,psoralen, etc.), those containing chelators (e.g., metals, radioactivemetals, boron, oxidative metals, etc.), those containing alkylators,those with modified linkages (e.g., alpha anomeric nucleic acids, etc.),as well as unmodified forms of the polynucleotides(s). Further, any ofthe hydroxyl groups ordinarily present in the sugars may be replaced,for example, by phosphonate groups, phosphate groups, protected bystandard protecting groups, or activated to prepare additional linkagesto additional nucleotides, or may be conjugated to solid or semi-solidsupports. The 5′ and 3′ terminal OH can be phosphorylated or substitutedwith amines or organic capping group moieties of from 1 to 20 carbonatoms. Other hydroxyls may also be derivatized to standard protectinggroups. Polynucleotides can also contain analogous forms of ribose ordeoxyribose sugars that are generally known in the art, including, forexample, 2′-O-methyl-, 2′-O-allyl-, 2′-fluoro- or 2′-azido-ribose,carbocyclic sugar analogs, α-anomeric sugars, epimeric sugars such asarabinose, xyloses or lyxoses, pyranose sugars, furanose sugars,sedoheptuloses, acyclic analogs, and basic nucleoside analogs such asmethyl riboside. One or more phosphodiester linkages may be replaced byalternative linking groups. These alternative linking groups include,but are not limited to, embodiments wherein phosphate is replaced byP(O)S (“thioate”), P(S)S (“dithioate”), (O)NR2 (“amidate”), P(O)R,P(O)OR′, CO, or CH2 (“formacetal”), in which each R or R′ isindependently H or substituted or unsubstituted alkyl (1-20 C)optionally containing an ether (—O—) linkage, aryl, alkenyl, cycloalkyl,cycloalkenyl or araldyl. Not all linkages in a polynucleotide need beidentical. The preceding description applies to all polynucleotidesreferred to herein, including RNA and DNA.

A “host cell” includes an individual cell or cell culture that can be orhas been a recipient for vector(s) for incorporation of polynucleotideinserts. Host cells include progeny of a single host cell, and theprogeny may not necessarily be completely identical (in morphology or ingenomic DNA complement) to the original parent cell due to natural,accidental, or deliberate mutation. A host cell includes cellstransfected in vivo with a polynucleotide(s) of this invention.

“Carriers” as used herein include pharmaceutically acceptable carriers,excipients, or stabilizers that are nontoxic to the cell or mammal beingexposed thereto at the dosages and concentrations employed. Often thephysiologically acceptable carrier is an aqueous pH buffered solution.Examples of physiologically acceptable carriers include buffers such asphosphate, citrate, and other organic acids; antioxidants includingascorbic acid; low molecular weight (less than about 10 residues)polypeptide; proteins, such as serum albumin, gelatin, orimmunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone;amino acids such as glycine, glutamine, asparagine, arginine or lysine;monosaccharides, disaccharides, and other carbohydrates includingglucose, mannose, or dextrins; chelating agents such as EDTA; sugaralcohols such as mannitol or sorbitol; salt-forming counterions such assodium; and/or nonionic surfactants such as TWEEN™, polyethylene glycol(PEG), and PLURONICS™.

The term “about” as used herein refers to the usual error range for therespective value readily known to the skilled person in this technicalfield. Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse.

As used herein and in the appended claims, the singular forms “a,” “an,”and “the” include plural reference unless the context clearly indicatesotherwise. For example, reference to an “antibody” is a reference tofrom one to many antibodies, such as molar amounts, and includesequivalents thereof known to those skilled in the art, and so forth.

It is understood that aspect and embodiments of the present disclosuredescribed herein include “comprising,” “consisting,” and “consistingessentially of” aspects and embodiments.

Overview

The present disclosure relates to anti-TREM2 antibodies (e.g.,monoclonal antibodies) with improved affinity and functionalcharacteristics; methods of making and using such antibodies;pharmaceutical compositions containing such antibodies; nucleic acidsencoding such antibodies; and host cells containing nucleic acidsencoding such antibodies.

Accordingly, certain aspects of the present disclosure are based, atleast in part, on the identification of anti-TREM2 antibodies that arecapable of binding to both human and cynomolgus monkey TREM2 with highaffinity (see, e.g., Examples 2 and 6); that are capable of binding toprimary human immune cells with high affinity (see, e.g., Examples 1-3);that have improved capability of clustering and activating TREM2signaling in vitro and in vivo (see, e.g., Examples 3, 7, and 11); andthat have improved capability of increase immune cell survival in vitro(see, e.g., Examples 3 and 9). Advantageously, anti-TREM2 antibodies ofthe present disclosure were shown have improved in vivo half-lives andto be able decreases plasma levels of soluble TREM2 in vitro and in vivo(see, e.g., Examples 4, 8, and 10). In some embodiments, anti-TREM2antibodies of the present disclosure induce, increase, or otherwiseenhance one or more TREM2 activities of the present disclosure. In someembodiments, anti-TREM2 antibodies of the present disclosure have one ormore of these improved affinity and functional characteristics, ascompared to an anti-TREM2 antibody having the heavy chain variableregion and light chain variable region of antibody AL2p-h50 or AL2p-h77.Moreover, based on the results described in Examples 2-11, thefunctional characteristics of affinity matured anti-TREM2 antibodies ofthe present disclosure, would not have been predictable from theirimproved affinity for TREM2.

In some embodiments, anti-TREM2 antibodies of the present disclosurehave high affinity for TREM2 exhibit the following functionalproperties: the ability to elevate TREM2 signaling both in soluble andin plate-bound format; the ability to promote survival of primary humanmacrophages and primary human dendritic cells; the ability to reduceproduction of soluble TREM2 (sTREM2) both in vitro by primary humanmyeloid cells and in vivo; and have relatively low polyspecificreactivity (PSR), which is a measure of unspecific binding. As disclosedherein, affinity maturation can lead to anti-TREM2 antibody variantsthat have both increased binding affinity and increased PSR (i.e.,relatively high unspecific binding). While certain antibodies of thepresent disclosure, such as AL2p-31 and AL2p-60, have higher bindingaffinity and better functional properties than other affinity maturedantibody variants, these also exhibit high PSR and have high levels ofbackground binding to cells (see, e.g., Example 12). Surprisingly,antibodies AL2p-58 and AL2p-47 exhibit both high binding affinity andrelatively low PSR as compared to other high affinity antibody variants,such as AL2p-31 and AL2p-60, while also having the ability to elevateTREM2 signaling both in soluble and in plate-bound format, to promotesurvival of primary human macrophages and primary human dendritic cells;and to reduce production of soluble TREM2 (sTREM2) both in vitro byprimary human myeloid cells and in vivo (see, e.g., Examples 2-12).Based on these results, it was unexpected that antibodies AL2p-58 andAL2p-47 exhibit high affinity to TREM2 and good functional propertieswithout showing any significant PSR or background binding to cells.

The results in Example 9 also surprisingly show that affinity maturedanti-TREM2 antibodies of the present disclosure, such as AL2p-58 andAL2p-47, induce a several hundred-fold increase in cell viability ofprimary human macrophages and dendritic cells (see, e.g., Table 14 andFIGS. 8A and 8B). This functional property is surprising, as affinitymatured anti-TREM2 antibodies, such as AL2p-58 and AL2p-47, exhibit onlyapproximately a 10-fold improvement in affinity (K_(D)) for binding tohuman TREM2-Fc as compared to the parental mouse anti-TREM2 antibodyAL2p (see, e.g., Tables 1 and 8), but have a several hundred-foldincrease in their ability to promote cell viability. In addition, it issurprising that antibody AL2p-37, which has approximately similarbinding affinity than AL2p-58 and AL2p-47, has relatively lower potencythan AL2p-58 and AL2p-47 for promoting cell viability.

TREM2 Proteins

In one aspect, the present disclosure provides antibodies that bind to aTREM2 protein of the present disclosure with improved affinity andinduce one or more TREM2 activities and/or enhance one or more TREM2activities after binding to a TREM2 protein expressed in a cell.

TREM2 proteins of the present disclosure include, without limitation, ahuman TREM2 protein (Uniprot Accession No. Q9NZC2; SEQ ID NO: 1), and anon-human mammalian TREM2 protein, such as mouse TREM2 protein (UniprotAccession No. Q99NH8; SEQ ID NO: 2), rat TREM2 protein (UniprotAccession No. D3ZZ89; SEQ ID NO: 3), Rhesus monkey TREM2 protein(Uniprot Accession No. F6QVF2; SEQ ID NO: 4), cynomolgus monkey TREM2protein (NCBI Accession No. XP_015304909.1; SEQ ID NO: 5), equine TREM2protein (Uniprot Accession No. F7D6L0; SEQ ID NO: 6), pig TREM2 protein(Uniprot Accession No. H2EZZ3; SEQ ID NO: 7), and dog TREM2 protein(Uniprot Accession No. E2RP46; SEQ ID NO: 8). As used herein “TREM2protein” refers to both wild-type sequences and naturally occurringvariant sequences.

Triggering receptor expressed on myeloid cells-2 (TREM2) is variouslyreferred to as TREM-2, TREM2a, TREM2b, TREM2c, triggering receptorexpressed on myeloid cells-2a, and triggering receptor expressed onmonocytes-2. TREM2 is a 230 amino acid membrane protein. TREM2 is animmunoglobulin-like receptor primarily expressed on myeloid lineagecells, including without limitation, macrophages, dendritic cells,monocytes, Langerhans cells of skin, Kupffer cells, osteoclasts, andmicroglia. In some embodiments, TREM2 forms a receptor signaling complexwith DAP12. In some embodiments, TREM2 phosphorylates and signalsthrough DAP12 (an ITAM domain adaptor protein). In some embodimentsTREM2 signaling results in the downstream activation of PI3K or otherintracellular signals. On Myeloid cells, Toll-like receptor (TLR)signals are important for the activation of TREM2 activities, e.g., inthe context of an infection response. TLRs also play a key role in thepathological inflammatory response, e.g., TLRs expressed in macrophagesand dendritic cells.

In some embodiments, an example of a human TREM2 amino acid sequence isset forth below as SEQ ID NO: 1:

        10         20         30         40MEPLRLLILL FVTELSGAHN TTVFQGVAGQ SLQVSCPYDS        50         60         70         80MKHWGRRKAW CRQLGEKGPC QRVVSTHNLW LLSFLRRWNG        90        100        110        120STAITDDTLG GTLTITLRNL QPHDAGLYQC QSLHGSEADT       130        140        150        160LRKVLVEVLA DPLDHRDAGD LWFPGESESF EDAHVEHSIS       170        180        190        200RSLLEGEIPF PPTSILLLLA CIFLIKILAA SALWAAAWHG       210        220        230  QKPGTHPPSE LDCGHDPGYQ LQTLPGLRDT

In some embodiments, the human TREM2 is a preprotein that includes asignal peptide. In some embodiments, the human TREM2 is a matureprotein. In some embodiments, the mature TREM2 protein does not includea signal peptide. In some embodiments, the mature TREM2 protein isexpressed on a cell. In some embodiments, TREM2 contains a signalpeptide located at amino acid residues 1-18 of human TREM2 (SEQ ID NO:1); an extracellular immunoglobulin-like variable-type (IgV) domainlocated at amino acid residues 29-112 of human TREM2 (SEQ ID NO: 1);additional extracellular sequences located at amino acid residues113-174 of human TREM2 (SEQ ID NO: 1); a transmembrane domain located atamino acid residues 175-195 of human TREM2 (SEQ ID NO: 1); and anintracellular domain located at amino acid residues 196-230 of humanTREM2 (SEQ ID NO: 1).

The transmembrane domain of human TREM2 contains a lysine at amino acidresidue 186 that can interact with an aspartic acid in DAP12, which is akey adaptor protein that transduces signaling from TREM2, TREM1, andother related IgV family members.

Homologues of human TREM2 include, without limitation, the naturalkiller (NK) cell receptor NK-p44 (NCTR2), the polymeric immunoglobulinreceptor (pIgR), CD300E, CD300A, CD300C, and TREML1/TLT1. In someembodiments, NCTR2 has similarity with TREM2 within the IgV domain.

Anti-TREM2 Antibodies

Certain aspects of the present disclosure relate to antibodies (e.g.,monoclonal antibodies) that specifically bind to TREM2 with improvedaffinity. In some embodiments, antibodies of the present disclosure binda mature TREM2 protein. In some embodiments, antibodies of the presentdisclosure bind a mature TREM2 protein, wherein the mature TREM2 proteinis expressed on a cell. In some embodiments, antibodies of the presentdisclosure bind a TREM2 protein expressed on one or more human cellsselected from human dendritic cells, human macrophages, human monocytes,human osteoclasts, human Langerhans cells of skin, human Kupffer cells,human microglia, and any combinations thereof.

In some embodiments, anti-TREM2 antibodies of the present disclosurebind to a TREM2 protein without competing with, inhibiting, or otherwiseblocking one or more TREM2 ligands from binding to the TREM2 protein.Examples of suitable TREM2 ligands include, without limitation, TREM2ligands expressed by E. coli cells, apoptotic cells, nucleic acids,anionic lipids, APOE, APOE2, APOE3, APOE4, anionic APOE, anionic APOE2,anionic APOE3, anionic APOE4, lipidated APOE, lipidated APOE2, lipidatedAPOE3, lipidated APOE4, zwitterionic lipids, negatively chargedphospholipids, phosphatidylserine, sulfatides, phosphatidylcholin,sphingomyelin, membrane phospholipids, lipidated proteins, proteolipids,lipidated peptides, and lipidated amyloid beta peptide. Accordingly, incertain embodiments, the one or more TREM2 ligands comprise E. colicells, apoptotic cells, nucleic acids, anionic lipids, zwitterioniclipids, negatively charged phospholipids, phosphatidylserine (PS),sulfatides, phosphatidylcholin, sphingomyelin (SM), phospholipids,lipidated proteins, proteolipids, lipidated peptides, and lipidatedamyloid beta peptide.

In some embodiments, anti-TREM2 antibodies of the present disclosure donot inhibit the growth of one or more innate immune cells. In someembodiments, anti-TREM2 antibodies of the present disclosure bind to oneor more primary immune cells with an affinity that is from five timeshigher to 100 times higher than an anti-TREM2 antibody selected from ananti-TREM2 antibody comprising a heavy chain variable region comprisingthe amino acid sequence of SEQ ID NO: 27 and comprising light chainvariable region comprising the amino acid sequence of SEQ ID NO: 56; ananti-TREM2 antibody comprising a heavy chain variable region comprisingthe amino acid sequence of SEQ ID NO: 91 and a light chain variableregion comprising the amino acid sequence of SEQ ID NO: 103; and ananti-TREM2 antibody comprising a heavy chain variable region comprisingthe amino acid sequence of SEQ ID NO: 119 and a light chain variableregion comprising the amino acid sequence of SEQ ID NO: 120. In someembodiments, anti-TREM2 antibodies of the present disclosure bind to oneor more primary immune cells with an affinity that is at least fivetimes higher, at least six times higher, at least seven times higher, atleast eight times higher, at least nine times higher, at least 10 timeshigher, at least 11 times higher, at least 12 times higher, at least 13times higher, at least 14 times higher, at least 15 times higher, atleast 16 times higher, at least 17 times higher, at least 18 timeshigher, at least 19 times higher, at least 20 times higher, at least 21times higher, at least 22 times higher, at least 23 times higher, atleast 24 times higher, at least 25 times higher, at least 26 timeshigher, at least 27 times higher, at least 28 times higher, at least 29times higher, at least 30 times higher, at least 35 times higher, atleast 40 times higher, at least 45 times higher, at least 50 timeshigher than an anti-TREM2 antibody selected from an anti-TREM2 antibodycomprising a heavy chain variable region comprising the amino acidsequence of SEQ ID NO: 27 and comprising light chain variable regioncomprising the amino acid sequence of SEQ ID NO: 56; an anti-TREM2antibody comprising a heavy chain variable region comprising the aminoacid sequence of SEQ ID NO: 91 and a light chain variable regioncomprising the amino acid sequence of SEQ ID NO: 103; and an anti-TREM2antibody comprising a heavy chain variable region comprising the aminoacid sequence of SEQ ID NO: 119 and a light chain variable regioncomprising the amino acid sequence of SEQ ID NO: 120. In someembodiments, anti-TREM2 antibodies of the present disclosure bind to oneor more primary immune cells with a mean fluorescence intensity (MFI)that ranges from 100 to 1500, or greater than 1500. In some embodiments,anti-TREM2 antibodies of the present disclosure bind to one or moreprimary immune cells with a mean fluorescence intensity (MFI) that is atleast 100, at least 110, at least 120, at least 130, at least 140, atleast 141, at least 150, at least 152, at least 155, at least 159, atleast 160, at least 170, at least 180, at least 187, at least 190, atleast 194, at least 195, at least 200, at least 210, at least 220, atleast 224, at least 230, at least 235, at least 240, at least 250, atleast 260, at least 262, at least 270, at least 280, at least 288, atleast 290, at least 296, at least 300, at least 310, at least 318, atleast 320, at least 322, at least 327, at least 330, at least 340, atleast 350, at least 360, at least 370, at least 372, at least 380, atleast 390, at least 400, at least 408, at least 410, at least 413, atleast 420, at least 430, at least 440, at least 450, at least 460, atleast 470, at least 480, at least 490, at least 499, at least 500, atleast 510, at least 520, at least 530, at least 534, at least 540, atleast 547, at least 550, at least 560, at least 570, at least 580, atleast 590, at least 600, at least 610, at least 620, at least 630, atleast 640, at least 650, at least 660, at least 662, at least 670, atleast 680, at least 690, at least 700, at least 710, at least 720, atleast 730, at least 740, at least 750, at least 760, at least 770, atleast 780, at least 790, at least 800, at least 810, at least 820, atleast 830, at least 840, at least 850, at least 860, at least 870, atleast 880, at least 890, at least 900, at least 910, at least 920, atleast 930, at least 940, at least 950, at least 960, at least 970, atleast 980, at least 990, at least 1000, at least 1035, at least 1110, atleast 1120, at least 1130, at least 1140, at least 1150, at least 1160,at least 1170, at least 1180, at least 1190, at least 1200, at least1210, at least 1220, at least 1230, at least 1240, at least 1250, atleast 1260, at least 1270, at least 1280, at least 1290, at least 1300,at least 1310, at least 1320, at least 1330, at least 1340, at least1350, at least 1360, at least 1370, at least 1380, at least 1390, atleast 1400, at least 1410, at least 1420, at least 1430, at least 1440,at least 1450, at least 1460, at least 1467, at least 1470, at least1480, at least 1490, or at least 1500. In some embodiments, the MFI isdetermined at a temperature of approximately 25° C. In some embodiments,the K_(D) is determined using a monovalent antibody (e.g., a Fab) or afull-length antibody in a monovalent form. Methods for the preparationand selection of antibodies that interact and/or bind with specificityto TREM2 are described herein. (e.g., see Examples 1 and 2).

In some embodiments, anti-TREM2 antibodies of the present disclosurecluster and activate TREM2 signaling in an amount that is at least0.5-fold greater, at least 0.6-fold greater, at least 0.7-fold greater,at least 0.8-fold greater, at least 0.9-fold greater, at least 1-foldgreater, at least 2-fold greater, at least 3-fold greater, at least4-fold greater, at least 5-fold greater, at least 6-fold greater, atleast 7-fold greater, at least 8-fold greater, at least 9-fold greater,or at least 10-fold greater than that of an anti-TREM2 antibody selectedfrom an anti-TREM2 antibody comprising a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO: 27 and comprising lightchain variable region comprising the amino acid sequence of SEQ ID NO:56; an anti-TREM2 antibody comprising a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO: 91 and a light chainvariable region comprising the amino acid sequence of SEQ ID NO: 103;and an anti-TREM2 antibody comprising a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO: 119 and a light chainvariable region comprising the amino acid sequence of SEQ ID NO: 120.

In some embodiments, anti-TREM2 antibodies of the present disclosurecluster and activate TREM2 signaling in an amount that ranges from about1-fold over control (FOC) to about 30-fold over control (FOC). In someembodiments, anti-TREM2 antibodies of the present disclosure cluster andactivate TREM2 signaling in an amount that is at least 1-fold overcontrol (FOC), at least 1.1-fold over control (FOC), at least 1.2-foldover control (FOC), at least 1.3-fold over control (FOC), at least1.4-fold over control (FOC), at least 1.5-fold over control (FOC), atleast 1.6-fold over control (FOC), at least 1.7-fold over control (FOC),at least 1.8-fold over control (FOC), at least 1.9-fold over control(FOC), at least 2-fold over control (FOC), at least 2.1-fold overcontrol (FOC), at least 2.2-fold over control (FOC), at least 2.3-foldover control (FOC), at least 2.4-fold over control (FOC), at least2.5-fold over control (FOC), at least 2.6-fold over control (FOC), atleast 2.7-fold over control (FOC), at least 2.8-fold over control (FOC),at least 2.9-fold over control (FOC), 3-fold over control (FOC), atleast 3.1-fold over control (FOC), at least 3.2-fold over control (FOC),at least 3.3-fold over control (FOC), at least 3.4-fold over control(FOC), at least 3.5-fold over control (FOC), at least 3.6-fold overcontrol (FOC), at least 3.7-fold over control (FOC), at least 3.8-foldover control (FOC), at least 3.9-fold over control (FOC), 4-fold overcontrol (FOC), at least 4.1-fold over control (FOC), at least 4.2-foldover control (FOC), at least 4.3-fold over control (FOC), at least4.4-fold over control (FOC), at least 4.5-fold over control (FOC), atleast 4.6-fold over control (FOC), at least 4.7-fold over control (FOC),at least 4.8-fold over control (FOC), at least 4.9-fold over control(FOC), 5-fold over control (FOC), at least 5.1-fold over control (FOC),at least 5.2-fold over control (FOC), at least 5.3-fold over control(FOC), at least 5.4-fold over control (FOC), at least 5.5-fold overcontrol (FOC), at least 5.6-fold over control (FOC), at least 5.7-foldover control (FOC), at least 5.8-fold over control (FOC), at least5.9-fold over control (FOC), 6-fold over control (FOC), at least6.1-fold over control (FOC), at least 6.2-fold over control (FOC), atleast 6.3-fold over control (FOC), at least 6.4-fold over control (FOC),at least 6.5-fold over control (FOC), at least 6.6-fold over control(FOC), at least 6.7-fold over control (FOC), at least 6.8-fold overcontrol (FOC), at least 6.9-fold over control (FOC), 7-fold over control(FOC), at least 7.1-fold over control (FOC), at least 7.2-fold overcontrol (FOC), at least 7.3-fold over control (FOC), at least 7.4-foldover control (FOC), at least 7.5-fold over control (FOC), at least7.6-fold over control (FOC), at least 7.7-fold over control (FOC), atleast 7.8-fold over control (FOC), at least 7.9-fold over control (FOC),8-fold over control (FOC), at least 8.1-fold over control (FOC), atleast 8.2-fold over control (FOC), at least 8.3-fold over control (FOC),at least 8.4-fold over control (FOC), at least 8.5-fold over control(FOC), at least 8.6-fold over control (FOC), at least 8.7-fold overcontrol (FOC), at least 8.8-fold over control (FOC), at least 8.9-foldover control (FOC), 9-fold over control (FOC), at least 9.1-fold overcontrol (FOC), at least 9.2-fold over control (FOC), at least 9.3-foldover control (FOC), at least 9.4-fold over control (FOC), at least9.5-fold over control (FOC), at least 9.6-fold over control (FOC), atleast 9.7-fold over control (FOC), at least 9.8-fold over control (FOC),at least 9.9-fold over control (FOC), at least 10-fold over control(FOC), at least 11-fold over control (FOC), at least 12-fold overcontrol (FOC), at least 13-fold over control (FOC), at least 14-foldover control (FOC), at least 15-fold over control (FOC), at least16-fold over control (FOC), at least 17-fold over control (FOC), atleast 18-fold over control (FOC), at least 19-fold over control (FOC),at least 20-fold over control (FOC), at least 21-fold over control(FOC), at least 22-fold over control (FOC), at least 23-fold overcontrol (FOC), at least 24-fold over control (FOC), at least 25-foldover control (FOC), at least 26-fold over control (FOC), at least27-fold over control (FOC), at least 28-fold over control (FOC), atleast 29-fold over control (FOC), or at least 30-fold over control(FOC). In some embodiments, clustering and activation of TREM2 signalingis determined at 37° C. using a monovalent antibody (e.g., a Fab) or afull-length antibody in a monovalent form. Methods for the measuringclustering and activation of TREM2 signaling are described herein (e.g.,see Example 3).

In some embodiments, anti-TREM2 antibodies of the present disclosureincrease immune cell survival in vitro that to an extent that is that isat least one and a half times higher, at least two times higher, atleast three times higher, at least four times higher, at least fivetimes higher, at least six times higher, at least seven times higher, atleast eight times higher, at least nine times higher, at least 10 timeshigher, at least 11 times higher, at least 12 times higher, at least 13times higher, at least 14 times higher, at least 15 times higher, atleast 16 times higher, at least 17 times higher, at least 18 timeshigher, at least 19 times higher, at least 20 times higher, at least 21times higher, at least 22 times higher, at least 23 times higher, atleast 24 times higher, at least 25 times higher, at least 26 timeshigher, at least 27 times higher, at least 28 times higher, at least 29times higher, at least 30 times higher, at least 35 times higher, atleast 40 times higher, at least 45 times higher, at least 50 timeshigher, at least 55 times higher, at least 60 times higher, at least 65times higher, at least 70 times higher, at least 75 times higher, atleast 80 times higher, at least 85 times higher, at least 90 timeshigher, at least 95 times higher, or at least 100 times higher than ananti-TREM2 antibody selected from an anti-TREM2 antibody comprising aheavy chain variable region comprising the amino acid sequence of SEQ IDNO: 27 and comprising light chain variable region comprising the aminoacid sequence of SEQ ID NO: 56; an anti-TREM2 antibody comprising aheavy chain variable region comprising the amino acid sequence of SEQ IDNO: 91 and a light chain variable region comprising the amino acidsequence of SEQ ID NO: 103; and an anti-TREM2 antibody comprising aheavy chain variable region comprising the amino acid sequence of SEQ IDNO: 119 and a light chain variable region comprising the amino acidsequence of SEQ ID NO: 120.

In some embodiments, the ability of anti-TREM2 antibodies of the presentdisclosure to increase immune cell survival in vitro is measured bydetermining the area under the curve (AUC) of growth curves of primaryimmune cells in culture that were treated with anti-TREM2 antibodies ofthe present disclosure. In some embodiments, anti-TREM2 antibodies ofthe present disclosure increase immune cell survival in vitro with anAUC that ranges from about 200000 to about 1500000. In some embodiments,anti-TREM2 antibodies of the present disclosure increase immune cellsurvival in vitro with an AUC that is at least 200000, at least 210000,at least 220000, at least 230000, at least 240000, at least 250000, atleast 260000, at least 270000, at least 280000, at least 290000, atleast 300000, at least 310000, at least 320000, at least 330000, atleast 340000, at least 350000, at least 360000, at least 370000, atleast 380000, at least 390000, at least 400000, at least 410000, atleast 420000, at least 430000, at least 440000, at least 450000, atleast 460000, at least 470000, at least 480000, at least 490000, atleast 500000, at least 510000, at least 520000, at least 530000, atleast 540000, at least 550000, at least 560000, at least 570000, atleast 580000, at least 590000, at least 600000, at least 610000, atleast 620000, at least 630000, at least 640000, at least 650000, atleast 660000, at least 670000, at least 680000, at least 690000, atleast 700000, at least 710000, at least 720000, at least 730000, atleast 740000, at least 750000, at least 760000, at least 770000, atleast 780000, at least 790000, at least 800000, at least 810000, atleast 820000, at least 830000, at least 840000, at least 850000, atleast 860000, at least 870000, at least 880000, at least 890000, atleast 900000, at least 910000, at least 920000, at least 930000, atleast 940000, at least 950000, at least 960000, at least 970000, atleast 980000, at least 990000, at least 1000000, at least 1010000, atleast 1020000, at least 1030000, at least 1040000, at least 1050000, atleast 1060000, at least 1070000, at least 1080000, at least 1090000, atleast 1100000, at least 1110000, at least 1120000, at least 1130000, atleast 1140000, at least 1150000, at least 1160000, at least 1170000, atleast 1180000, at least 1190000, at least 1200000, at least 1210000, atleast 1220000, at least 1230000, at least 1240000, at least 1250000, atleast 1260000, at least 1270000, at least 1280000, at least 1290000, atleast 1300000, at least 1310000, at least 1320000, at least 1330000, atleast 1340000, at least 1350000, at least 1360000, at least 1370000, atleast 1380000, at least 1390000, at least 1400000, at least 1410000, atleast 1420000, at least 1430000, at least 1440000, at least 1450000, atleast 1460000, at least 1470000, at least 1480000, at least 1490000, orat least 1500000. In some embodiments, immune cell survival in vitro ismeasured at 4° C. using a monovalent antibody (e.g., a Fab) or afull-length antibody in a monovalent form. Methods for measuring immunecell survival in vitro are described herein (e.g., see Example 3).

In some embodiments, anti-TREM2 antibodies of the present disclosurehave an in vivo half-life that is lower than a human control IgG1antibody. In some embodiments, anti-TREM2 antibodies of the presentdisclosure have an in vivo half-life that is at least one and a halftimes lower, at least two times lower, at least three times lower, atleast four times lower, at least five times lower, at least six timeslower, at least seven times lower, at least eight times lower, at leastnine times lower, at least 10 times lower, at least 11 times lower, atleast 12 times lower, at least 13 times lower, at least 14 times lower,at least 15 times lower, at least 16 times lower, at least 17 timeslower, at least 18 times lower, at least 19 times lower, at least 20times lower, at least 21 times lower, at least 22 times lower, at least23 times lower, at least 24 times lower, at least 25 times lower, atleast 26 times lower, at least 27 times lower, at least 28 times lower,at least 29 times lower, at least 30 times lower, at least 35 timeslower, at least 40 times lower, at least 45 times lower, at least 50times lower, at least 55 times lower, at least 60 times lower, at least65 times lower, at least 70 times lower, at least 75 times lower, atleast 80 times lower, at least 85 times lower, at least 90 times lower,at least 95 times lower, or at least 100 times lower than an anti-TREM2antibody selected from an anti-TREM2 antibody comprising a heavy chainvariable region comprising the amino acid sequence of SEQ ID NO: 27 andcomprising light chain variable region comprising the amino acidsequence of SEQ ID NO: 56; an anti-TREM2 antibody comprising a heavychain variable region comprising the amino acid sequence of SEQ ID NO:91 and a light chain variable region comprising the amino acid sequenceof SEQ ID NO: 103; and an anti-TREM2 antibody comprising a heavy chainvariable region comprising the amino acid sequence of SEQ ID NO: 119 anda light chain variable region comprising the amino acid sequence of SEQID NO: 120.

In some embodiments, anti-TREM2 antibodies of the present disclosurehave an in vivo half-life that ranges from about 0.1 days to about 10days. In some embodiments, anti-TREM2 antibodies of the presentdisclosure have an in vivo half-life that is about 0.1 days, about 0.2days, about 0.3 days, about 0.4 days, about 0.5 days, about 0.6 days,about 0.7 days, about 0.8 days, about 0.9 days, about 1 day, about 1.1days, about 1.2 days, about 1.3 days, about 1.4 days, about 1.5 days,about 1.6 days, about 1.7 days, about 1.8 days, about 1.9 days, about 2days, about 2.1 days, about 2.2 days, about 2.3 days, about 2.4 days,about 2.5 days, about 2.6 days, about 2.7 days, about 2.8 days, about2.9 days, about 3 days, about 3.1 days, about 3.2 days, about 3.3 days,about 3.4 days, about 3.5 days, about 3.6 days, about 3.7 days, about3.8 days, about 3.9 days, about 4 days, about 4.1 days, about 4.2 days,about 4.3 days, about 4.4 days, about 4.5 days, about 4.6 days, about4.7 days, about 4.8 days, about 4.9 days, about 5 days, about 5.1 days,about 5.2 days, about 5.3 days, about 5.4 days, about 5.5 days, about5.6 days, about 5.7 days, about 5.8 days, about 5.9 days, about 6 days,about 6.1 days, about 6.2 days, about 6.3 days, about 6.4 days, about6.5 days, about 6.6 days, about 6.7 days, about 6.8 days, about 6.9days, about 7 days, about 7.1 days, about 7.2 days, about 7.3 days,about 7.4 days, about 7.5 days, about 7.6 days, about 7.7 days, about7.8 days, about 7.9 days, about 8 days, about 8.1 days, about 8.2 days,about 8.3 days, about 8.4 days, about 8.5 days, about 8.6 days, about8.7 days, about 8.8 days, about 8.9 days, about 9 days, about 9.1 days,about 9.2 days, about 9.3 days, about 9.4 days, about 9.5 days, about9.6 days, about 9.7 days, about 9.8 days, about 9.9 days, or about 10days. In some embodiments, in vivo half-life is measured using amonovalent antibody (e.g., a Fab) or a full-length antibody in amonovalent form. Methods for measuring in vivo half-life are describedherein (e.g., see Example 4).

Anti-TREM2 antibodies of the present disclosure generally bind with highaffinity to one or more TREM2 proteins expressed on a cell. For example,the TREM2 receptor is thought to require clustering on the cell surfacein order to transduce a signal. Thus agonist antibodies may have uniquefeatures to stimulate, for example, the TREM2 receptor. For example,they may have the correct epitope specificity that is compatible withreceptor activation, as well as the ability to induce or retain receptorclustering on the cell surface. In addition, anti-TREM2 antibodies ofthe present disclosure may display the ability to bind TREM2 withoutblocking simultaneous binding of one or more TREM2 ligands. Theanti-TREM2 antibodies of the present disclosure may further displayadditive and/or synergistic functional interactions with one or moreTREM2 ligands. Thus, in some embodiments, the maximal activity of TREM2when bound to anti-TREM2 antibodies of the present disclosure incombination with one or more TREM2 ligands of the present disclosure maybe greater (e.g., enhanced) than the maximal activity of TREM2 whenexposed to saturating concentrations of ligand alone or to saturatingconcentrations of the antibody alone. In addition, the activity of TREM2at a given concentration of TREM2 ligand may be greater (e.g., enhanced)in the presence of the antibody. Accordingly, in some embodiments,anti-TREM2 antibodies of the present disclosure have an additive effectwith the one or more TREM2 ligands to enhance the one or more TREM2activities when bound to the TREM2 protein. In some embodiments,anti-TREM2 antibodies of the present disclosure synergize with the oneor more TREM2 ligands to enhance the one or more TREM2 activities. Insome embodiments, anti-TREM2 antibodies of the present disclosureincrease the potency of the one or more TREM2 ligands to induce the oneor more TREM2 activities, as compared to the potency of the one or moreTREM2 ligands to induce the one or more TREM2 activities in the absenceof the antibody. In some embodiments, anti-TREM2 antibodies of thepresent disclosure enhance the one or more TREM2 activities in theabsence of cell surface clustering of TREM2. In some embodiments,anti-TREM2 antibodies of the present disclosure enhance the one or moreTREM2 activities by inducing or retaining cell surface clustering ofTREM2. In some embodiments, anti-TREM2 antibodies of the presentdisclosure are clustered by one or more Fc-gamma receptors expressed onone or more immune cells, including without limitation, B cells andmicroglial cells. In some embodiments, enhancement of the one or moreTREM2 activities induced by binding of one or more TREM2 ligands to theTREM2 protein is measured on primary cells, including withoutlimitation, dendritic cells, bone marrow-derived dendritic cells,monocytes, microglia, macrophages, neutrophils, NK cells, osteoclasts,Langerhans cells of skin, and Kupffer cells, or on cell lines, and theenhancement of the one or more TREM2 activities induced by binding ofone or more TREM2 ligands to the TREM2 protein is measured, for example,utilizing an in vitro cell assay.

In vivo, anti-TREM2 antibodies of the present disclosure may activatereceptors by multiple potential mechanisms. In some embodiments,anti-TREM2 antibodies of the present disclosure, have, due to thecorrect epitope specificity, the ability to activate TREM2 in solutionwithout having to be clustered with a secondary antibody, bound onplates, or clustered through Fcg receptors. In some embodiments,anti-TREM2 antibodies of the present disclosure have isotypes of humanantibodies, such as IgG2, that have, due to their unique structure, anintrinsic ability to cluster receptors or retain receptors in aclustered configuration, thereby activating receptors such as TREM2without binding to an Fc receptor (e.g., White et al., (2015) CancerCell 27, 138-148).

In some embodiments, anti-TREM2 antibodies of the present disclosurecluster receptors (e.g., TREM2) by binding to Fcg receptors on adjacentcells. Binding of the constant IgG Fc part of the antibody to Fcgreceptors leads to aggregation of the antibodies, and the antibodies inturn aggregate the receptors to which they bind through their variableregion (Chu et al (2008) Mol Immunol, 45:3926-3933; and Wilson et al.,(2011) Cancer Cell 19, 101-113). Binding to the inhibitory Fcg receptorFcgR (FcgRIIB) that does not elicit cytokine secretion, oxidative burst,increased phagocytosis, and enhanced antibody-dependent, cell-mediatedcytotoxicity (ADCC) is often a preferred way to cluster antibodies invivo, since binding to FcgRIIB is not associated with immune adverseeffects. Any suitable assay described herein may be used to determineantibody clustering.

Other mechanisms may also be used to cluster receptors (e.g., TREM2).For example, in some embodiments, antibody fragments (e.g., Fabfragments) that are cross-linked together may be used to clusterreceptors (e.g., TREM2) in a manner similar to antibodies with Fcregions that bind Fcg receptors, as described above. In someembodiments, cross-linked antibody fragments (e.g., Fab fragments) mayfunction as agonist antibodies if they induce receptor clustering on thecell surface and bind an appropriate epitope on the target (e.g.,TREM2).

In some embodiments, antibodies of the present disclosure that bind aTREM2 protein may include antibodies that due to their epitopespecificity bind TREM2 and activate one or more TREM2 activities. Insome embodiments, such antibodies may bind to the ligand-binding site onTREM2 and mimic the action of one or more TREM2 ligands, or stimulatethe target antigen to transduce signal by binding to one or more domainsthat are not the ligand-binding sites. In some embodiments, theantibodies do not compete with or otherwise block ligand binding toTREM2. In some embodiments, the antibodies, act additively orsynergistically with one or more TREM2 ligands to activate and/orenhance one more TREM2 activities.

In some embodiments, TREM2 activities that may be induced and/orenhanced by anti-TREM2 antibodies of the present disclosure and/or oneor more TREM2 ligands of the present disclosure include, withoutlimitation, TREM2 binding to DAP12; DAP12 phosphorylation; activation ofSyk kinase; modulation of one or more pro-inflammatory mediatorsselected from IFN-β, IL-1α, IL-1β, TNF-α, IL-6, IL-8, CRP, CD86,MCP-1/CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, IL-20 familymembers, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF-1, OPN, CD11c, GM-CSF,IL-11, IL-12, IL-17, IL-18, and IL-23, where the modulation may occursin one or more cells selected from macrophages, M1 macrophages,activated M1 macrophages, M2 macrophages, dendritic cells, monocytes,osteoclasts, Langerhans cells of skin, Kupffer cells, and microglialcells; recruitment of Syk to a DAP12/TREM2 complex; increasing activityof one or more TREM2-dependent genes, where the one or moreTREM2-dependent genes comprise nuclear factor of activated T-cells(NFAT) transcription factors; increased survival of dendritic cells,macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages,monocytes, osteoclasts, Langerhans cells of skin, Kupffer cells,microglia, M1 microglia, activated M1 microglia, and M2 microglia, orany combination thereof; modulated expression of one or more stimulatorymolecules selected from CD83, CD86 MHC class II, CD40, and anycombination thereof, where the CD40 may be expressed on dendritic cells,monocytes, macrophages, or any combination thereof, and where thedendritic cells may comprise bone marrow-derived dendritic cells;increasing memory; and reducing cognitive deficit.

As used herein, an anti-TREM2 antibody of the present disclosureenhances one or more TREM2 activities induced by binding of one or moreTREM2 ligands to the TREM2 protein if it induces at least a 2-fold, atleast a 3-fold, at least a 4-fold, at least a 5-fold, at least a 6-fold,at least a 7-fold, at least a 8-fold, at least a 9-fold, at least a10-fold, at least an 11-fold, at least a 12-fold, at least a 13-fold, atleast a 14-fold, at least a 15-fold, at least a 16-fold, at least a17-fold, at least an 18-fold, at least a 19-fold, at least a 20-fold orgreater increase in the one or more TREM2 activities as compared tolevels of the one or more TREM2 activities induced by binding of one ormore TREM2 ligands to the TREM2 protein in the absence of the anti-TREM2antibody. In some embodiments, the increase in one more TEM2 activitiesmay be measured by any suitable in vitro cell-based assays or suitablein vivo model described herein or known in the art, for example, byutilizing a luciferase-based reporter assay to measure TREM2-dependentgene expression, using Western blot analysis to measure increase inTREM2-induced phosphorylation of downstream signaling partners, such asSyk, or by utilizing flow cytometry, such as fluorescence-activated cellsorting (FACS) to measure changes in cell surface levels of markers ofTREM2 activation. Any in vitro cell-based assays or suitable in vivomodel described herein or known in the art may be used to measureinteraction (e.g., binding) between TREM2 and one or more TREM2 ligands.

In some embodiments an anti-TREM2 antibody of the present disclosureenhances one or more TREM2 activities induced by binding of a TREM2ligand to the TREM2 protein if it induces an increase that ranges fromabout 1-fold to about 6-fold, or more than 6-fold in ligand-inducedTREM2-dependent gene transcription when used at a concentration thatranges from about 0.5 nM to about 50 nM, or greater than 50 nM, and ascompared to the level of TREM2-dependent gene transcription induced bybinding of the TREM2 ligand to the TREM2 protein in the absence of theanti-TREM2 antibody when the TREM2 ligand is used at its EC₅₀concentration. In some embodiments the increase in ligand-inducedTREM2-dependent gene transcription is at least 1-fold, at least 2-fold,at least a 3-fold, at least a 4-fold, at least a 5-fold, at least a6-fold, at least a 7-fold, at least a 8-fold, at least a 9-fold, atleast a 10-fold, at least an 11-fold, at least a 12-fold, at least a13-fold, at least a 14-fold, at least a 15-fold, at least a 16-fold, atleast a 17-fold, at least an 18-fold, at least a 19-fold, at least a20-fold or greater when used at a concentration that ranges from about0.5 nM to about 50 nM, or greater than 50 nM, and as compared to thelevel of TREM2-dependent gene transcription induced by binding of theTREM2 ligand to the TREM2 protein in the absence of the anti-TREM2antibody when the TREM2 ligand is used at its EC₅₀ concentration. Insome embodiments, the anti-TREM2 antibody is used at a concentration ofat least 0.5 nM, at least 0.6 nM, at least 0.7 nM, at least 0.8 nM, atleast 0.9 nM, at least 1 nM, at least 2 nM, at least 3 nM, at least 4nM, at least 5 nM, at least 6 nM, at least 7 nM, at least 8 nM, at least9 nM, at least 10 nM, at least 15 nM, at least 20 nM, at least 25 nM, atleast 30 nM, at least 35 nM, at least 40 nM, at least 45 nM, at least 46nM, at least 47 nM, at least 48 nM, at least 49 nM, or at least 50 nM.In some embodiments, the TREM2 ligand is phosphatidylserine (PS). Insome embodiments, the TREM2 ligand is sphingomyelin (SM). In someembodiments, the increase in one more TEM2 activities may be measured byany suitable in vitro cell-based assays or suitable in vivo modeldescribed herein or known in the art. In some embodiments, aluciferase-based reporter assay is used to measure the fold increase ofligand-induced TREM2-dependent gene expression in the presence andabsence of antibody.

As used herein, an anti-TREM2 antibody of the present disclosure doesnot compete with, inhibit, or otherwise block the interaction (e.g.,binding) between one or more TREM2 ligands and TREM2 if it decreasesligand binding to TREM2 by less than 20% at saturating antibodyconcentrations utilizing any in vitro assay or cell-based culture assaydescribed herein or known in the art. In some embodiments, anti-TREM2antibodies of the present disclosure inhibit interaction (e.g., binding)between one or more TREM2 ligands and TREM2 by less than 20%, less than19%, less than 18%, less than 17%, less than 16%, less than 15%, lessthan 14%, less than 13%, less than 12%, less than 11%, less than 10%,less than 9%, less than 8%, less than 7%, less than 6%, less than 5%,less than 4%, less than 3%, less than 2%, or less than 1% at saturatingantibody concentrations utilizing any in vitro assay or cell-basedculture assay described herein or known in the art.

In some embodiments, an anti-TREM2 antibody of the present disclosureinduces one or more TREM2 activities. In some embodiments, the antibodyinduces one or more activities of TREM2 after binding to a TREM2 proteinthat is expressed on a cell. In some embodiments, the antibody inducesone or more activities of TREM2 after binding to a soluble TREM2 proteinthat is not bound to the cell membrane. In certain embodiments, theTREM2 protein is expressed on a cell surface. In certain embodiments,soluble TREM2 protein (sTREM2) may be found, without limitation, inextracellular milieu, in blood serum, in cerebrospinal fluid (CSF), andin the interstitial space within tissues. In certain embodiments,soluble TREM2 protein (sTREM2) is non-cellular. In some embodiments asoluble TREM2 (sTREM2) protein of the present disclosure corresponds toamino acid residues 19-160 of SEQ ID NO:1. In some embodiments a solubleTREM2 (sTREM2) protein of the present disclosure corresponds to aminoacid residues 19-159 of SEQ ID NO:1. In some embodiments a soluble TREM2(sTREM2) protein of the present disclosure corresponds to amino acidresidues 19-158 of SEQ ID NO:1. In some embodiments a soluble TREM2(sTREM2) protein of the present disclosure corresponds to amino acidresidues 19-157 of SEQ ID NO: 1. In some embodiments a soluble TREM2(sTREM2) protein of the present disclosure corresponds to amino acidresidues 19-156 of SEQ ID NO:1. In some embodiments a soluble TREM2(sTREM2) protein of the present disclosure corresponds to amino acidresidues 19-155 of SEQ ID NO: 1. In some embodiments a soluble TREM2(sTREM2) protein of the present disclosure corresponds to amino acidresidues 19-154 of SEQ ID NO:1.

In some embodiments, soluble TREM2 (sTREM2) proteins of the presentdisclosure may be inactive variants of cellular TREM2 receptors. In someembodiments, sTREM2 may be present in the periphery, such as in theplasma, or brains of subject.

In some embodiments, anti-TREM2 antibodies of the present disclosuredecrease plasma levels of soluble TREM2 in vivo. In some embodiments,anti-TREM2 antibodies of the present disclosure decrease plasma levelsof soluble TREM2 in vivo by blocking cleavage, by inhibiting one or moremetalloproteases, or by inducing internalization.

In some embodiments, anti-TREM2 antibodies of the present disclosuredecrease plasma levels of soluble TREM2 in vivo by an amount that rangesfrom about 5% greater to about 50% greater than that of a human controlIgG1 antibody. In some embodiments, anti-TREM2 antibodies of the presentdisclosure decreases plasma levels of soluble TREM2 in vivo by an amountthat is at least 5%, at least 6%, at least 7%, at least 8%, at least 9%,at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, atleast 15%, at least 16%, at least 17%, at least 18%, at least 19%, atleast 20%, at least 21%, at least 22%, at least 23%, at least 24%, atleast 25%, at least 26%, at least 27%, at least 28%, at least 29%, atleast 30%, at least 31%, at least 32%, at least 33%, at least 34%, atleast 35%, at least 36%, at least 37%, at least 38%, at least 39%, atleast 40%, at least 41%, at least 42%, at least 43%, at least 44%, atleast 45%, at least 46%, at least 47%, at least 48%, at least 49%, or atleast 50% greater than that of a human control IgG1 antibody.

In some embodiments, anti-TREM2 antibodies of the present disclosuredecrease plasma levels of soluble TREM2 in vivo such that the plasmalevel of soluble TREM2 as a percentage of baseline six days of afterantibody treatment is at least 5%, at least 6%, at least 7%, at least8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%,at least 14%, at least 15%, at least 16%, at least 17%, at least 18%, atleast 19%, at least 20%, at least 21%, at least 22%, at least 23%, atleast 24%, at least 25%, at least 26%, at least 27%, at least 28%, atleast 29%, at least 30%, at least 31%, at least 32%, at least 33%, atleast 34%, at least 35%, at least 36%, at least 37%, at least 38%, atleast 39%, at least 40%, at least 41%, at least 42%, at least 43%, atleast 44%, at least 45%, at least 46%, at least 47%, at least 48%, atleast 49%, at least 50%, at least 51%, at least 52%, at least 53%, atleast 54%, at least 55%, at least 56%, at least 57%, at least 58%, atleast 59%, at least 60%, at least 61%, at least 62%, at least 63%, atleast 64%, at least 65%, at least 66%, at least 67%, at least 68%, atleast 69%, at least 70%, at least 71%, at least 72%, at least 73%, atleast 74%, at least 75%, at least 76%, at least 77%, at least 78%, atleast 79%, or at least 80%. In some embodiments, plasma levels ofsoluble TREM2 in vivo are measured using a monovalent antibody (e.g., aFab) or a full-length antibody in a monovalent form. Methods formeasuring plasma levels of soluble TREM2 in vivo are described herein(e.g., see Example 4).

Anti-TREM2 antibodies of the present disclosure can be used to prevent,reduce risk of, or treat dementia, frontotemporal dementia, Alzheimer'sdisease, vascular dementia, mixed dementia, Creutzfeldt-Jakob disease,normal pressure hydrocephalus, amyotrophic lateral sclerosis,Huntington's disease, tauopathy disease, Nasu-Hakola disease, stroke,acute trauma, chronic trauma, cognitive deficit, memory loss, lupus,acute and chronic colitis, rheumatoid arthritis, wound healing, Crohn'sdisease, inflammatory bowel disease, ulcerative colitis, obesity,malaria, essential tremor, central nervous system lupus, Behcet'sdisease, Parkinson's disease, dementia with Lewy bodies, multiple systematrophy, Shy-Drager syndrome, progressive supranuclear palsy, corticalbasal ganglionic degeneration, acute disseminated encephalomyelitis,granulomartous disorders, sarcoidosis, diseases of aging, seizures,spinal cord injury, traumatic brain injury, age related maculardegeneration, glaucoma, retinitis pigmentosa, retinal degeneration,respiratory tract infection, sepsis, eye infection, systemic infection,lupus, arthritis, multiple sclerosis, low bone density, osteoporosis,osteogenesis, osteopetrotic disease, Paget's disease of bone, solid andblood cancer, bladder cancer, brain cancer, breast cancer, colon cancer,rectal cancer, endometrial cancer, kidney cancer, renal cell cancer,renal pelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin'slymphoma, pancreatic cancer, prostate cancer, ovarian cancer,fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloid leukemia(AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia(CML), multiple myeloma, polycythemia vera, essential thrombocytosis,primary or idiopathic myelofibrosis, primary or idiopathicmyelosclerosis, myeloid-derived tumors, tumors that express TREM2,thyroid cancer, infections, CNS herpes, parasitic infections,Trypanosome infection, Cruzi infection, Pseudomonas aeruginosainfection, Leishmania donovani infection, group B Streptococcusinfection, Campylobacter jejuni infection, Neisseria meningiditisinfection, type I HIV, and Haemophilus influenza. The methods providedherein also find use in inducing or promoting the survival, maturation,functionality, migration, or proliferation of one or more immune cellsin an individual in need thereof. The methods provided herein findfurther use in decreasing the activity, functionality, or survival ofregulatory T cells, tumor-imbedded immunosuppressor dendritic cells,tumor-imbedded immunosuppressor macrophages, myeloid-derived suppressorcells, tumor-associated macrophages, acute myeloid leukemia (AML) cells,chronic lymphocytic leukemia (CLL) cell, or chronic myeloid leukemia(CML) cell in an individual in need thereof. The methods provided hereinfind further use in increasing memory and/or reducing cognitive deficit.

The anti-TREM2 antibodies of the present disclosure may also be used inadvanced wound care. In some embodiments, the anti-TREM2 antibodies ofthe present disclosure are monoclonal antibodies. Anti-TREM2 antibodiesof the present disclosure may be tested for inducing one or more TREM2activities. Useful assays may include western blots (e.g., fortyrosine-phosphorylated DAP12 or threonine/serine-phosphorylatedPI3K-kinase substrates), ELISA (e.g., for secreted interleukin orcytokine secretion), FACS (e.g., for anti-TREM2 binding to TREM2),immunocytochemistry (e.g., for e.g., for tyrosine-phosphorylated DAP12or threonine/serine-phosphorylated PI3K-kinase substrates),reporter-gene assays (e.g., for TLR activation), increased survivaland/or function of dendritic cells, macrophages, monocytes, osteoclasts,Langerhans cells of skin, Kupffer cells, and/or microglia, increasedphagocytosis of apoptotic neurons, damaged synapses, amyloid beta orfragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein,prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase,ataxin, Lewy body, atrial natriuretic factor, islet amyloid polypeptide,insulin, apolipoprotein AI, serum amyloid A, medin, prolactin,transthyretin, lysozyme, beta 2 microglobulin, gelsolin,keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein,Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat(DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline(GP) repeat peptides, glycine-arginine (GR) repeat peptides,proline-alanine (PA) repeat peptides, and proline-arginine (PR) repeatpeptides, nerve tissue debris, non-nerve tissue debris, bacteria, otherforeign bodies, disease-causing proteins, disease-causing peptides,disease-causing nucleic acid, or tumor cells by macrophages, dendriticcells, Langerhans cells of skin, Kupffer cells, monocytes, osteoclasts,and/or microglial cells, increased cytoskeleton reorganization, anddecreased microglial pro-inflammatory responses, or other assays knownin the art.

An antibody dependent on binding to FcgR receptor to activate targetedreceptors may lose its agonist activity if engineered to eliminate FcgRbinding (see, e.g., Wilson et al., (2011) Cancer Cell 19, 101-113;Armour at al., (2003) Immunology 40 (2003) 585-593); and White et al.,(2015) Cancer Cell 27, 138-148). As such, it is thought that ananti-TREM2 antibody of the present disclosure with the correct epitopespecificity can activate the target antigen, with minimal adverseeffects, when the antibody has an Fc domain from a human IgG2 isotype(CH1 and hinge region) or another type of Fc domain that is capable ofpreferentially binding the inhibitory FcgRIIB r receptors, or avariation thereof.

Exemplary antibody Fc isotypes and modifications are provided in Table Abelow. In some embodiments, the antibody has an Fc isotype listed inTable A below.

TABLE A Exemplary antibody Fc isotypes that are capableof binding Fc gamma receptor Fc Isotype Mutation (EU numbering scheme)IgG1 N297A IgG1 D265A and N297A IgG1 D270A IgG1 L234A and L235AL234A and G237A L234A and L235A and G237A IgG1P238D and/or L328E and/or S267E/L328Fand/or E233 and/or G237D and/or H268D and/or P271G and/or A330R IgG1P238D and L328E and E233D and G237D and H268D and P271G and A330R IgG1P238D and L328E and G237D and H268D and P271G and A330R IgG1P238D and S267E and L328F and E233D and G237D and H268D and P271G and A330R IgG1 P238D and S267E and L328F and G237D and H268D and P271G and A330R IgG2 V234A and G237A IgG4L235A and G237A and E318A IgG4 S228P and L236E IgG2/4IgG2 aa 118 to 260 and IgG4 aa 261  hybrid to 447H268Q and V309L; and A330S and P331S IgG1C226S and C229S and E233P and L234V  and L235A IgG1L234F and L235E and P331S IgG2 C232S or C233S IgG2 A330S and P331S IgG1S267E, and L328F S267E alone IgG2 S267E and L328F IgG4 S267E and L328FIgG2 WT HC with Kappa (light chain) LC HC C127S with Kappa LCKappa LC C214S Kappa LC C214S and HC C233S Kappa LC C214S and HC C232SAny of the above listed mutations  together with A330S and P331S mutations  F(ab′)2 fragment of WT IgG1 andany of the above listed mutations IgG1 Substitute the Constant Heavy 1  (CH1) and hinge region of IgG1 With   CH1 and hinge region of IGg2ASTKGPSVFP LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSSGLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP (SEQ ID NO: 145)With a Kappa LC IgG1 Any of the above listed mutations together with A330L/A330S and/or   L234F and/or L235E and/or P331SIgGl, IgG2,  Any of the above listed mutations  or IgG4together with M252Y and/or S254T and/or T256E Mouse IgG1For mouse disease models IgG4 WT IgG1 Any of the above listed mutation together with E430G, E430S, E430F, E430T, E345K, E345Q, E345R, E345Y, S440Y, S440W and/or any combination thereof. IgG2Any of the above listed mutation  together with E430G, E430S, E430F,E430T, E345K, E345Q, E345R, E345Y,  S440Y, S440W and/or any combinationthereof.

In addition to the isotypes described in Table A, and without wishing tobe bound to theory, it is thought that antibodies with human IgG1 orIgG3 isotypes and mutants thereof (e.g. Strohl (2009) Current Opinion inBiotechnology 2009, 20:685-691) that bind the activating Fcg ReceptorsI, IIA, IIC, IIIA, IIIB in human and/or Fcg Receptors I, III and IV inmouse, may also act as agonist antibodies in vivo but may be associatedwith adverse effects related to ADCC. However, such Fcg receptors appearto be less available for antibody binding in vivo, as compared to theInhibitory Fcg receptor FcgRIIB (see, e.g., White, et al., (2013) CancerImmunol. Immunother. 62, 941-948; and Li et al., (2011) Science333(6045):1030-1034.).

In some embodiments, the antibody is of the IgG class, the IgM class, orthe IgA class. In some embodiments, the antibody has an IgG1, IgG2,IgG3, or IgG4 isotype.

In certain embodiments, the antibody has an IgG2 isotype. In someembodiments, the antibody contains a human IgG2 constant region. In someembodiments, the human IgG2 constant region includes an Fc region. Insome embodiments, the antibody induces the one or more TREM2 activities,the DAP12 activities, or both independently of binding to an Fcreceptor. In some embodiments, the antibody binds an inhibitory Fcreceptor. In certain embodiments, the inhibitory Fc receptor isinhibitory Fc-gamma receptor IIB (FcγIIB). In some embodiments, the Fcregion contains one or more modifications. For example, in someembodiments, the Fc region contains one or more amino acid substitutions(e.g., relative to a wild-type Fc region of the same isotype). In someembodiments, the one or more amino acid substitutions are selected fromV234A (Alegre et al., (1994) Transplantation 57:1537-1543. 31; Xu etal., (2000) Cell Immunol, 200:16-26), G237A (Cole et al. (1999)Transplantation, 68:563-571), H268Q, V309L, A330S, P331S (US2007/0148167; Armour et al. (1999) Eur J Immunol 29: 2613-2624; Armouret al. (2000) The Haematology Journal 1(Suppl. 1):27; Armour et al.(2000) The Haematology Journal 1(Suppl.1):27), C232S, and/or C233S(White et al., (2015) Cancer Cell 27, 138-148), S267E, L328F (Chu etal., (2008) Mol Immunol, 45:3926-3933), M252Y, S254T, and/or T256E,where the amino acid position is according to the EU or, Kabat numberingconvention.

In some embodiments, the antibody has an IgG2 isotype with a heavy chainconstant domain that contains a C127S amino acid substitution, where theamino acid position is according to the EU or, Kabat numberingconvention (White et al., (2015) Cancer Cell 27, 138-148; Lightle etal., (2010) PROTEIN SCIENCE 19:753-762; and WO2008079246).

In some embodiments, the antibody has an IgG2 isotype with a Kappa lightchain constant domain that contains a C214S amino acid substitution,where the amino acid position is according to the EU or, Kabat numberingconvention (White et al., (2015) Cancer Cell 27, 138-148; Lightle etal., (2010) PROTEIN SCIENCE 19:753-762; and WO2008079246).

In certain embodiments, the antibody has an IgG1 isotype. In someembodiments, the antibody contains a mouse IgG1 constant region. In someembodiments, the antibody contains a human IgG1 constant region. In someembodiments, the human IgG1 constant region includes an Fc region. Insome embodiments, the antibody binds an inhibitory Fc receptor. Incertain embodiments, the inhibitory Fc receptor is inhibitory Fc-gammareceptor IIB (FcγIIB). In some embodiments, the Fc region contains oneor more modifications. For example, in some embodiments, the Fc regioncontains one or more amino acid substitutions (e.g., relative to awild-type Fc region of the same isotype). In some embodiments, the oneor more amino acid substitutions are selected from N297A (Bolt S et al.(1993) Eur J Immunol 23:403-411), D265A (Shields et al. (2001) R. J.Biol. Chem. 276, 6591-6604), L234A, L235A (Hutchins et al. (1995) ProcNatl Acad Sci USA, 92:11980-11984; Alegre et al., (1994) Transplantation57:1537-1543. 31; Xu et al., (2000) Cell Immunol, 200:16-26), G237A(Alegre et al. (1994) Transplantation 57:1537-1543. 31; Xu et al. (2000)Cell Immunol, 200:16-26), C226S, C229S, E233P, L234V, L234F, L235E(McEarchern et al., (2007) Blood, 109:1185-1192), P331S (Sazinsky etal., (2008) Proc Natl Acad Sci USA 2008, 105:20167-20172), S267E, L328F,A330L, M252Y, S254T, and/or T256E, where the amino acid position isaccording to the EU or, Kabat numbering convention.

In some embodiments, the antibody includes an IgG2 isotype heavy chainconstant domain 1(CH1) and hinge region (White et al., (2015) CancerCell 27, 138-148). In certain embodiments, the IgG2 isotype CH1 andhinge region contain the amino acid sequence ofASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCP (SEQ ID NO: 145). Insome embodiments, the antibody Fc region contains a S267E amino acidsubstitution, a L328F amino acid substitution, or both, and/or a N297Aor N297Q amino acid substitution, where the amino acid position isaccording to the EU or, Kabat numbering convention.

In certain embodiments, the antibody has an IgG4 isotype. In someembodiments, the antibody contains a human IgG4 constant region. In someembodiments, the human IgG4 constant region includes an Fc region. Insome embodiments, the antibody binds an inhibitory Fc receptor. Incertain embodiments, the inhibitory Fc receptor is inhibitory Fc-gammareceptor IIB (FcγIIB). In some embodiments, the Fc region contains oneor more modifications. For example, in some embodiments, the Fc regioncontains one or more amino acid substitutions (e.g., relative to awild-type Fc region of the same isotype). In some embodiments, the oneor more amino acid substitutions are selected from L235A, G237A, S228P,L236E (Reddy et al., (2000) J Immunol, 164:1925-1933), S267E, E318A,L328F, M252Y, S254T, and/or T256E, where the amino acid position isaccording to the EU or, Kabat numbering convention.

In certain embodiments, the antibody has a hybrid IgG2/4 isotype. Insome embodiments, the antibody includes an amino acid sequencecontaining amino acids 118 to 260 according to EU or, Kabat numbering ofhuman IgG2 and amino acids 261-447 according to EU or, Kabat numberingof human IgG4 (WO 1997/11971; WO 2007/106585).

In certain embodiments, the antibody contains a mouse IgG4 constantregion (Bartholomaeus, et al. (2014). J. Immunol. 192, 2091-2098).

In some embodiments, the Fc region further contains one or moreadditional amino acid substitutions selected from A330L, L234F; L235E,or P331S according to EU or, Kabat numbering; and any combinationthereof.

In certain embodiments, the antibody contains one or more amino acidsubstitutions in the Fc region at a residue position selected fromC127S, L234A, L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S,E345R, E430G, S440Y, and any combination thereof, where the numbering ofthe residues is according to EU or Kabat numbering. In some embodiments,the Fc region contains an amino acid substitution at positions E430G,L243A, L235A, and P331S, where the numbering of the residue position isaccording to EU numbering. In some embodiments, the Fc region containsan amino acid substitution at positions E430G and P331S, where thenumbering of the residue position is according to EU numbering. In someembodiments, the Fc region contains an amino acid substitution atpositions E430G and K322A, where the numbering of the residue positionis according to EU numbering. In some embodiments, the Fc regioncontains an amino acid substitution at positions E430G, A330S, andP331S, where the numbering of the residue position is according to EUnumbering. In some embodiments, the Fc region contains an amino acidsubstitution at positions E430G, K322A, A330S, and P331S, where thenumbering of the residue position is according to EU numbering. In someembodiments, the Fc region contains an amino acid substitution atpositions E430G, K322A, and A330S, where the numbering of the residueposition is according to EU numbering. In some embodiments, the Fcregion contains an amino acid substitution at positions E430G, K322A,and P331S, where the numbering of the residue position is according toEU numbering. In some embodiments, the Fc region contains an amino acidsubstitution at positions S267E and L328F, where the numbering of theresidue position is according to EU numbering. In some embodiments, theFc region contains an amino acid substitution at position C127S, wherethe numbering of the residue position is according to EU numbering. Insome embodiments, the Fc region contains an amino acid substitution atpositions E345R, E430G and S440Y, where the numbering of the residueposition is according to EU numbering.

Further IgG Mutations

In some embodiments, one or more of the IgG1 variants described hereinmay be combined with an A330L mutation (Lazar et al., (2006) Proc NatlAcad Sci USA, 103:4005-4010), or one or more of L234F, L235E, and/orP331S mutations (Sazinsky et al., (2008) Proc Natl Acad Sci USA,105:20167-20172), where the amino acid position is according to the EUor, Kabat numbering convention, to eliminate complement activation. Insome embodiments, the IgG variants described herein may be combined withone or more mutations to enhance the antibody half-life in human serum(e.g. M252Y, S254T, T256E mutations according to the EU or, Kabatnumbering convention) (Dall'Acqua et al., (2006) J Biol Chem,281:23514-23524; and Strohl e al., (2009) Current Opinion inBiotechnology, 20:685-691).

In some embodiments, an IgG4 variant of the present disclosure may becombined with an S228P mutation according to the EU or, Kabat numberingconvention (Angal et al., (1993) Mol Immunol, 30:105-108) and/or withone or more mutations described in Peters et al., (2012) J Biol Chem.13; 287(29):24525-33) to enhance antibody stabilization.

Exemplary Anti-TREM2 Antibodies

In some embodiments, an isolated anti-TREM2 antibody of the presentdisclosure binds to TREM2 with high affinity and enhances one or moreTREM2 activities induced by binding of one or more TREM2 ligands to theTREM2 protein, as compared to the one or more TREM2 activities inducedby binding of the one or more TREM2 ligands to the TREM2 protein in theabsence of the isolated antibody. In some embodiments, the anti-TREM2antibody enhances the one or more TREM2 activities without competingwith or otherwise blocking binding of the one or more TREM2 ligands tothe TREM2 protein. In some embodiments, the antibody is a humanizedantibody, a bispecific antibody, a multivalent antibody, or a chimericantibody. Exemplary descriptions of such antibodies are found throughoutthe present disclosure. In some embodiments, the antibody is abispecific antibody recognizing a first antigen and a second antigen.

In some embodiments, anti-TREM2 antibodies of the present disclosurebind to a human TREM2, or a homolog thereof, including withoutlimitation a mammalian (e.g., non-human mammalian) TREM2 protein, mouseTREM2 protein (Uniprot Accession No. Q99NH8), rat TREM2 protein (UniprotAccession No. D3ZZ89), Rhesus monkey TREM2 protein (Uniprot AccessionNo. F6QVF2), cynomolgus monkey TREM2 protein (NCBI Accession No.XP_015304909.1), equine TREM2 protein (Uniprot Accession No. F7D6L0),pig TREM2 protein (Uniprot Accession No. H2EZZ3), and dog TREM2 protein(Uniprot Accession No. E2RP46). In some embodiments, anti-TREM2antibodies of the present disclosure specifically bind to human TREM2.In some embodiments, anti-TREM2 antibodies of the present disclosurespecifically bind to cynomolgus monkey TREM2. In some embodiments,anti-TREM2 antibodies of the present disclosure specifically bind toboth human TREM2 and cynomolgus monkey TREM2. In some embodiments,anti-TREM2 antibodies of the present disclosure induce at least oneTREM2 activity of the present disclosure.

Anti-TREM2 Antibody-Binding Regions

Certain aspects of the preset disclosure relate to anti-TREM2 antibodiesthat bind to an epitope of human TREM2 that is the same as or overlapswith the TREM2 epitope bound by an anti-TREM2 antibody comprising aheavy chain variable region comprising the amino acid sequence of SEQ IDNO: 119 and a light chain variable region comprising the amino acidsequence of SEQ ID NO: 120. In some embodiments, anti-TREM2 antibodiesof the present disclosure bind essentially the same TREM2 epitope boundby an anti-TREM2 antibody comprising a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO: 119 and a light chainvariable region comprising the amino acid sequence of SEQ ID NO: 120. Insome embodiments, anti-TREM2 antibodies of the present disclosure bindto one or more amino acids within amino acid residues SFEDAHVEH (aminoacid residues 149-157 of SEQ ID NO: 1). In some embodiments, anti-TREM2antibodies of the present disclosure bind to one or more amino acidresidues selected from E151, D152, and E156 of SEQ ID NO: 1. In someembodiments, anti-TREM2 antibodies of the present disclosure bind aminoacid residues E151, D152, and E156 of SEQ ID NO: 1.

In some embodiments, anti-TREM2 antibodies of the present disclosurecompetitively inhibit binding of an anti-TREM2 antibody comprising aheavy chain variable region comprising the amino acid sequence of SEQ IDNO: 119 and a light chain variable region comprising the amino acidsequence of SEQ ID NO: 120. In some embodiments, anti-TREM2 antibodiesof the present disclosure compete with an anti-TREM2 antibody comprisinga heavy chain variable region comprising the amino acid sequence of SEQID NO: 119 and a light chain variable region comprising the amino acidsequence of SEQ ID NO: 120 for binding to TREM2.

In some embodiments, anti-TREM2 antibodies of the present disclosurecompetitively inhibit binding of at least one antibody selected from anyof the antibodies listed in Tables 2A-2C, 3A-3C, 4A-4D, 5A-5D, 6, and 7.In some embodiments, anti-TREM2 antibodies of the present disclosurecompetitively inhibit binding of at least one antibody selected fromAL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8,AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16,AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24,AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32,AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40,AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48,AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56,AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-h19,AL2p-h21, AL2p-h22, AL2p-h23, AL2p-h24, AL2p-h25, AL2p-h26, AL2p-h27,AL2p-h28, AL2p-h29, AL2p-h30, AL2p-h31, AL2p-h32, AL2p-h33, AL2p-h34,AL2p-h35, AL2p-h36, AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47, AL2p-h59,AL2p-h76, and AL2p-h90. In some embodiments, anti-TREM2 antibodies ofthe present disclosure competitively inhibit binding of antibodyAL2p-31. In some embodiments, anti-TREM2 antibodies of the presentdisclosure competitively inhibit binding of antibody AL2p-37. In someembodiments, anti-TREM2 antibodies of the present disclosurecompetitively inhibit binding of antibody AL2p-47. In some embodiments,anti-TREM2 antibodies of the present disclosure competitively inhibitbinding of antibody AL2p-58. In some embodiments, anti-TREM2 antibodiesof the present disclosure competitively inhibit binding of antibodyAL2p-60. In some embodiments, anti-TREM2 antibodies of the presentdisclosure competitively inhibit binding of antibody AL2p-61. In someembodiments, anti-TREM2 antibodies of the present disclosurecompetitively inhibit binding of antibody AL2p-62.

In some embodiments, anti-TREM2 antibodies of the present disclosurebind to an epitope of human TREM2 that is the same as or overlaps withthe TREM2 epitope bound by at least one antibody selected from any ofthe antibodies listed in Tables 2A-2C, 3A-3C, 4A-4D, 5A-5D, 6, and 7. Insome embodiments, anti-TREM2 antibodies of the present disclosure bindto an epitope of human TREM2 that is the same as or overlaps with theTREM2 epitope bound by at least one antibody selected from AL2p-h50,AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10,AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18,AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26,AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77,AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42,AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50,AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58,AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p-h22,AL2p-h23, AL2p-h24, AL2p-h25, AL2p-h26, AL2p-h27, AL2p-h28, AL2p-h29,AL2p-h30, AL2p-h31, AL2p-h32, AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36,AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47, AL2p-h59, AL2p-h76, andAL2p-h90. In some embodiments, anti-TREM2 antibodies of the presentdisclosure bind to an epitope of human TREM2 that is the same as oroverlaps with the TREM2 epitope bound by antibody AL2p-31. In someembodiments, anti-TREM2 antibodies of the present disclosure bind to anepitope of human TREM2 that is the same as or overlaps with the TREM2epitope bound by antibody AL2p-37. In some embodiments, anti-TREM2antibodies of the present disclosure bind to an epitope of human TREM2that is the same as or overlaps with the TREM2 epitope bound by antibodyAL2p-47. In some embodiments, anti-TREM2 antibodies of the presentdisclosure bind to an epitope of human TREM2 that is the same as oroverlaps with the TREM2 epitope bound by antibody AL2p-58. In someembodiments, anti-TREM2 antibodies of the present disclosure bind to anepitope of human TREM2 that is the same as or overlaps with the TREM2epitope bound by antibody AL2p-60. In some embodiments, anti-TREM2antibodies of the present disclosure bind to an epitope of human TREM2that is the same as or overlaps with the TREM2 epitope bound by antibodyAL2p-61. In some embodiments, anti-TREM2 antibodies of the presentdisclosure bind to an epitope of human TREM2 that is the same as oroverlaps with the TREM2 epitope bound by antibody AL2p-62.

In some embodiments, anti-TREM2 antibodies of the present disclosurebind essentially the same TREM2 epitope bound by at least one antibodyselected from any of the antibodies listed in Tables 2A-2C, 3A-3C,4A-4D, 5A-5D, 6, and 7. In some embodiments, anti-TREM2 antibodies ofthe present disclosure bind essentially the same TREM2 epitope bound byat least one antibody selected from AL2p-h50, AL2p-2, AL2p-3, AL2p-4,AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12,AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20,AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28,AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36,AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44,AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52,AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60,AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p-h22, AL2p-h23, AL2p-h24,AL2p-h25, AL2p-h26, AL2p-h27, AL2p-h28, AL2p-h29, AL2p-h30, AL2p-h31,AL2p-h32, AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36, AL2p-h42, AL2p-h43,AL2p-h44, AL2p-h47, AL2p-h59, AL2p-h76, and AL2p-h90. Detailed exemplarymethods for mapping an epitope to which an antibody binds are providedin Morris (1996) “Epitope Mapping Protocols,” in Methods in MolecularBiology vol. 66 (Humana Press, Totowa, N.J.). In some embodiments,anti-TREM2 antibodies of the present disclosure bind essentially thesame TREM2 epitope bound by antibody AL2p-31. In some embodiments,anti-TREM2 antibodies of the present disclosure bind essentially thesame TREM2 epitope bound by antibody AL2p-37. In some embodiments,anti-TREM2 antibodies of the present disclosure bind essentially thesame TREM2 epitope bound by antibody AL2p-47. In some embodiments,anti-TREM2 antibodies of the present disclosure bind essentially thesame TREM2 epitope bound by antibody AL2p-58. In some embodiments,anti-TREM2 antibodies of the present disclosure bind essentially thesame TREM2 epitope bound by antibody AL2p-60. In some embodiments,anti-TREM2 antibodies of the present disclosure bind essentially thesame TREM2 epitope bound by antibody AL2p-61. In some embodiments,anti-TREM2 antibodies of the present disclosure bind essentially thesame TREM2 epitope bound by antibody AL2p-62.

In some embodiments, anti-TREM2 antibodies of the present disclosurecompete with one or more antibodies selected from AL2p-h50, AL2p-2,AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10,AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18,AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26,AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77,AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42,AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50,AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58,AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p-h22,AL2p-h23, AL2p-h24, AL2p-h25, AL2p-h26, AL2p-h27, AL2p-h28, AL2p-h29,AL2p-h30, AL2p-h31, AL2p-h32, AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36,AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47, AL2p-h59, AL2p-h76, andAL2p-h90, and any combination thereof for binding to TREM2. In someembodiments, anti-TREM2 antibodies of the present disclosure competewith antibody AL2p-31 for binding to TREM2 for binding to TREM2. In someembodiments, anti-TREM2 antibodies of the present disclosure competewith antibody AL2p-37 for binding to TREM2. In some embodiments,anti-TREM2 antibodies of the present disclosure compete with antibodyAL2p-47 for binding to TREM2. In some embodiments, anti-TREM2 antibodiesof the present disclosure compete with antibody AL2p-58 for binding toTREM2. In some embodiments, anti-TREM2 antibodies of the presentdisclosure compete with antibody AL2p-60 for binding to TREM2. In someembodiments, anti-TREM2 antibodies of the present disclosure competewith antibody AL2p-61 for binding to TREM2. In some embodiments,anti-TREM2 antibodies of the present disclosure compete with antibodyAL2p-62 for binding to TREM2.

In an exemplary competition assay, immobilized TREM2 or cells expressingTREM2 on the cell surface are incubated in a solution comprising a firstlabeled antibody that binds to TREM2 (e.g., human or non-human primate)and a second unlabeled antibody that is being tested for its ability tocompete with the first antibody for binding to TREM2. The secondantibody may be present in a hybridoma supernatant. As a control,immobilized TREM2 or cells expressing TREM2 is incubated in a solutioncomprising the first labeled antibody but not the second unlabeledantibody. After incubation under conditions permissive for binding ofthe first antibody to TREM2, excess unbound antibody is removed, and theamount of label associated with immobilized TREM2 or cells expressingTREM2 is measured. If the amount of label associated with immobilizedTREM2 or cells expressing TREM2 is substantially reduced in the testsample relative to the control sample, then that indicates that thesecond antibody is competing with the first antibody for binding toTREM2. See, Harlow and Lane (1988) Antibodies: A Laboratory Manual ch.14 (Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.).

Anti-TREM2 Antibody Light Chain and Heavy Chain Variable Regions

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise (a) a heavy chain variable region comprising at least one, two,or three HVRs selected from HVR-H1, HVR-H2, and HVR-H3 of any one of theantibodies listed in Tables 2A-2C, or selected from AL2p-2, AL2p-3,AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13,AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21,AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29,AL2p-30, AL2p-31, AL2p-32, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39,AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47,AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55,AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, or AL2p-62, andany combination thereof; and/or (b) a light chain variable regioncomprising at least one, two, or three HVRs selected from HVR-H1,HVR-H2, and HVR-H3 of any one of the antibodies listed in Tables 3A-3C,or selected from AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10,AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18,AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26,AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-38,AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46,AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54,AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, orAL2p-62, and any combination thereof. In some embodiments, the HVR-H1,HVR-H2, HVR-H3, HVR-L1, HVR-L2, and HVR-L3 comprise EU or Kabat HVR,Chothia HVR, or Contact HVR sequences as shown in Tables 2A-2C, 3A-3C,6, and 7, or from an antibody selected from AL2p-2, AL2p-3, AL2p-4,AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12,AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20,AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28,AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-35, AL2p-36, AL2p-37,AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45,AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53,AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61,or AL2p-62, and any combination thereof.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable region and a light chain variableregion, wherein the heavy chain variable region comprises: an HVR-H1comprising the sequence according to Formula I: YAFX₁X₂X₃WMN, wherein X₁is S or W, X₂ is S, L, or R, and X₃ is S, D, H, Q, or E (SEQ ID NO:121); an HVR-H2 comprising the sequence according to Formula II:RIYPGX₁GX₂TNYAX₃KX₄X₅G, wherein X₁ is D, G, E, Q, or V, X₂ is D or Q, X₃is Q, R, H, W, Y, or G, X₄ is F, R, or W, and X₅ is Q, R, K, or H (SEQID NO: 122); and an HVR-H3 comprising the sequence according to FormulaIII: ARLLRNX₁PGX₂SYAX₃DY, wherein X₁ is Q or K, X₂ is E, S, or A, and X₃is M or H (SEQ ID NO: 123), and wherein the antibody is not an antibodycomprising a heavy chain variable region comprising an HVR-H1 comprisingthe sequence of YAFSSSWMN (SEQ ID NO: 124), an HVR-H2 comprising thesequence of RIYPGDGDTNYAQKFQG (SEQ ID NO: 125), and an HVR-H3 comprisingthe sequence of ARLLRNQPGESYAMDY (SEQ ID NO: 126).

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable region and a light chain variableregion, wherein the light chain variable region comprises: an HVR-L1comprising the sequence according to Formula IV: RX₁SX₂SLX₃HSNX₄YTYLH,wherein X₁ is S or T, X₂ is Q, R, or S, X₃ is V or I, and X₄ is G, R, W,Q, or A (SEQ ID NO: 127) an HVR-L2 comprising the sequence according toFormula V: KVSNRX₁S, wherein X₁ is F, R, V, or K (SEQ ID NO: 128); andan HVR-L3 comprising the sequence according to Formula V: SQSTRVPYT (SEQID NO: 129), and wherein the antibody is not an antibody comprising alight chain variable region comprising an HVR-L1 comprising the sequenceof RSSQSLVHSNGYTYLH (SEQ ID NO: 130), an HVR-L2 comprising the sequenceof KVSNRFS (SEQ ID NO: 131), and an HVR-L3 comprising the sequence ofSQSTRVPYT (SEQ ID NO: 129).

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable region and a light chain variableregion, wherein the heavy chain variable region comprises: an HVR-H1comprising the sequence according to Formula I, wherein X₁ is S or W, X₂is S, L, or R, and X₃ is S, D, H, Q, or E; an HVR-H2 comprising thesequence according to Formula II, wherein X₁ is D, G, E, Q, or V, X₂ isD or Q, X₃ is Q, R, H, W, Y, or G, X₄ is F, R, or W, and X₅ is Q, R, K,or H; and an HVR-H3 comprising the sequence according to Formula III,wherein X₁ is Q or K, X₂ is E, S, or A, and X₃ is M or H, and the lightchain variable region comprises: an HVR-L1 comprising the sequenceaccording to Formula IV, wherein X₁ is S or T, X₂ is Q, R, or S, X₃ is Vor I, and X₄ is G, R, W, Q, or A; an HVR-L2 comprising the sequenceaccording to Formula V, wherein X₁ is F, R, V, or K; and an HVR-L3comprising the sequence: SQSTRVPYT (SEQ ID NO: 129), and wherein theantibody is not an antibody comprising a heavy chain variable regioncomprising an HVR-H1 comprising the sequence of YAFSSSWMN (SEQ ID NO:124), an HVR-H2 comprising the sequence of RIYPGDGDTNYAQKFQG (SEQ ID NO:125), and an HVR-H3 comprising the sequence of ARLLRNQPGESYAMDY (SEQ IDNO: 126), and comprising a light chain variable region comprising anHVR-L1 comprising the sequence of RSSQSLVHSNGYTYLH (SEQ ID NO: 130), anHVR-L2 comprising the sequence of KVSNRFS (SEQ ID NO: 131), and anHVR-L3 comprising the sequence of SQSTRVPYT (SEQ ID NO: 129).

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises one or moreof: (a) an HVR-H1 comprising an amino acid sequence with at least 85%,at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, atleast 91%, at least 92%, at least 93%, at least 94%, at least 95%, atleast 96%, at least 97%, at least 98%, at least 99%, or 100% identity toan HVR-H1 amino acid sequence of antibody AL2p-2, AL2p-3, AL2p-4,AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14,AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22,AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30,AL2p-31, AL2p-32, AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40,AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48,AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56,AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, or AL2p-62; (b) an HVR-H2comprising an amino acid sequence with at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to an HVR-H2amino acid sequence of antibody AL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8,AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16,AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24,AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32,AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42,AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50,AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58,AL2p-59, AL2p-60, AL2p-61, or AL2p-62; and (c) an HVR-H3 comprising anamino acid sequence with at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to an HVR-H3 amino acidsequence of antibody AL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9,AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17,AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25,AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-35,AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43,AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51,AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59,AL2p-60, AL2p-61, or AL2p-62; and/or wherein the light chain variabledomain comprises one or more of: (a) an HVR-L1 comprising an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to an HVR-L1 amino acid sequence of antibodyAL2p-2, AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11,AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19,AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27,AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-35, AL2p-36, AL2p-37,AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45,AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53,AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61,or AL2p-62; (b) an HVR-L2 comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to an HVR-L1 amino acid sequence of antibody AL2p-2,AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12,AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20,AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28,AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-35, AL2p-36, AL2p-37, AL2p-38,AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46,AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54,AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, orAL2p-62; and (c) an HVR-L3 comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to an HVR-L3 amino acid sequence of antibody AL2p-2,AL2p-3, AL2p-4, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12,AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20,AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28,AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-35, AL2p-36, AL2p-37, AL2p-38,AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46,AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54,AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, orAL2p-62.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable region comprises an HVR-H1comprising the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), an HVR-H2comprising the amino acid sequence RIYPGGGDTNYARKFQG (SEQ ID NO: 133),an HVR-H3 comprising the amino acid sequence ARLLRNQPGESYAMDY (SEQ IDNO: 126), and the light chain variable region comprises an HVR-L1comprising the amino acid sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130), anHVR-L2 comprising the amino acid sequence KVSNRRS (SEQ ID NO: 134), andan HVR-L3 comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 129).In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable region comprises an HVR-H1comprising the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), an HVR-H2comprising the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135),an HVR-H3 comprising the amino acid sequence ARLLRNQPGESYAMDY (SEQ IDNO: 126), and the light chain variable region comprises an HVR-L1comprising the amino acid sequence RSSQSLVHSNGYTYLH (SEQ ID NO: 130), anHVR-L2 comprising the amino acid sequence KVSNRFS (SEQ ID NO: 131), andan HVR-L3 comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 129).In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable region comprises an HVR-H1comprising the amino acid sequence YAFSSDWMN (SEQ ID NO: 136), an HVR-H2comprising the amino acid sequence RIYPGEGDTNYARKFHG (SEQ ID NO: 137),an HVR-H3 comprising the amino acid sequence ARLLRNKPGESYAMDY (SEQ IDNO: 138), and the light chain variable region comprises an HVR-L1comprising the amino acid sequence RTSQSLVHSNAYTYLH (SEQ ID NO: 139), anHVR-L2 comprising the amino acid sequence KVSNRVS (SEQ ID NO: 140), andan HVR-L3 comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 129).In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable region comprises an HVR-H1comprising the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), an HVR-H2comprising the amino acid sequence RIYPGEGDTNYARKFQG (SEQ ID NO: 141),an HVR-H3 comprising the amino acid sequence ARLLRNQPGESYAMDY (SEQ IDNO: 126), and the light chain variable region comprises an HVR-L1comprising the amino acid sequence RSSQSLVHSNQYTYLH (SEQ ID NO: 142), anHVR-L2 comprising the amino acid sequence KVSNRRS (SEQ ID NO: 134), andan HVR-L3 comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 129).In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable region comprises an HVR-H1comprising the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), an HVR-H2comprising the amino acid sequence RIYPGEGDTNYAGKFQG (SEQ ID NO: 143),an HVR-H3 comprising the amino acid sequence ARLLRNQPGESYAMDY (SEQ IDNO: 126), and the light chain variable region comprises an HVR-L1comprising the amino acid sequence RSSQSLVHSNQYTYLH (SEQ ID NO: 142), anHVR-L2 comprising the amino acid sequence KVSNRFS (SEQ ID NO: 131), andan HVR-L3 comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 129).In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable region comprises an HVR-H1comprising the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), an HVR-H2comprising the amino acid sequence RIYPGGGDTNYAGKFQG (SEQ ID NO: 135),an HVR-H3 comprising the amino acid sequence ARLLRNQPGESYAMDY (SEQ IDNO: 126), and the light chain variable region comprises an HVR-L1comprising the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144), anHVR-L2 comprising the amino acid sequence KVSNRFS (SEQ ID NO: 131), andan HVR-L3 comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 129).In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable region comprises an HVR-H1comprising the amino acid sequence YAFSSQWMN (SEQ ID NO: 132), an HVR-H2comprising the amino acid sequence RIYPGGGDTNYARKFQG (SEQ ID NO: 133),an HVR-H3 comprising the amino acid sequence ARLLRNQPGESYAMDY (SEQ IDNO: 126), and the light chain variable region comprises an HVR-L1comprising the amino acid sequence RSSQSLVHSNRYTYLH (SEQ ID NO: 144), anHVR-L2 comprising the amino acid sequence KVSNRRS (SEQ ID NO: 134), andan HVR-L3 comprising the amino acid sequence SQSTRVPYT (SEQ ID NO: 129).In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable region and a light chain variableregion, wherein the heavy chain variable region comprises one, two,three or four frame work regions selected from VH FR1, VH FR2, VH FR3,and VH FR4, wherein: the VH FR1 comprises a sequence selected from thegroup consisting of SEQ ID NOs: 9-11, the VH FR2 comprises a sequenceselected from the group consisting of SEQ ID NOs: 12 and 13, the VH FR3comprises a sequence selected from the group consisting of SEQ ID NOs:14 and 15, and the VH FR4 comprises the sequence of SEQ ID NO: 16;and/or the light chain variable region comprises one, two, three or fourframe work regions selected from VL FR1, VL FR2, VL FR3, and VL FR4,wherein: the L FR1 comprises a sequence selected from the groupconsisting of SEQ ID NOs: 17-20, the VL FR2 comprises a sequenceselected from the group consisting of SEQ ID NOs: 21 and 22, the VL FR3comprises a sequence selected from the group consisting of SEQ ID NOs:23 and 24, and the VL FR4 comprises a sequence selected from the groupconsisting of SEQ ID NOs: 25 and 26.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable region of any one of the antibodieslisted in Table 6A, or selected from AL2p-h50, AL2p-2, AL2p-3, AL2p-4,AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12,AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20,AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28,AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36,AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44,AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52,AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60,AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p-h22, AL2p-h23, AL2p-h24,AL2p-h25, AL2p-h26, AL2p-h27, AL2p-h28, AL2p-h29, AL2p-h30, AL2p-h31,AL2p-h32, AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36, AL2p-h42, AL2p-h43,AL2p-h44, AL2p-h47, AL2p-h59, AL2p-h76, and AL2p-h90; and/or a lightchain variable region of any one of the antibodies listed in Table 7A,or selected from AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6,AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14,AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22,AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30,AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38,AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46,AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54,AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, AL2p-62,AL2p-h19, AL2p-h21, AL2p-h22, AL2p-h23, AL2p-h24, AL2p-h25, AL2p-h26,AL2p-h27, AL2p-h28, AL2p-h29, AL2p-h30, AL2p-h31, AL2p-h32, AL2p-h33,AL2p-h34, AL2p-h35, AL2p-h36, AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47,AL2p-h59, AL2p-h76, and AL2p-h90. In some embodiments, anti-TREM2antibodies of the present disclosure comprise a heavy chain variableregion comprising an amino acid sequence selected from any of SEQ IDNOs: 27-71 and 91; and/or a light chain variable domain comprising anamino acid sequence selected from any of SEQ ID NOs: 92-113 and 118. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable region comprising an amino acid sequenceselected from any of SEQ ID NOs: 27, 56 and 72-90; and/or a light chainvariable domain comprising an amino acid sequence selected from any ofSEQ ID NOs: 92, 104, and 114-117.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-2 or to the amino acid sequence of SEQ ID NO:28; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-2 or to the amino acid sequence of SEQ ID NO:92. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-2 or to the amino acid sequence of SEQ ID NO:28, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-2. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-2 or to the amino acid sequence of SEQ ID NO: 92, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-2. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-2 or to the amino acid sequence of SEQ ID NO:28 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-2 or the amino acid sequenceof SEQ ID NO: 28. In certain embodiments, a total of 1 to 5 amino acidshave been substituted, inserted and/or deleted in the heavy chainvariable domain amino acid sequence of antibody AL2p-2 or the amino acidsequence of SEQ ID NO: 28. In certain embodiments, substitutions,insertions, or deletions occur in regions outside the HVRs (i.e., in theFR regions). In some embodiments, the substitutions, insertions, ordeletions occur in in the FR regions. Optionally, the anti-TREM2antibody comprises the VH sequence of antibody AL2p-2 or of SEQ ID NO:28, including post-translational modifications of that sequence. In aparticular embodiment, the VH comprises one, two or three HVRs selectedfrom: (a) the HVR-H1 amino acid sequence of antibody AL2p-2, (b) theHVR-H2 amino acid sequence of antibody AL2p-2, and (c) the HVR-H3 aminoacid sequence of antibody AL2p-2. In some embodiments, anti-TREM2antibodies of the present disclosure comprise a light chain variabledomain (VL) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a light chain variabledomain amino acid sequence of antibody AL2p-2 or to the amino acidsequence of SEQ ID NO: 92 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the lightchain variable domain amino acid sequence of antibody AL2p-2 or theamino acid sequence of SEQ ID NO: 92. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in thelight chain variable domain amino acid sequence of antibody AL2p-2 orthe amino acid sequence of SEQ ID NO: 92. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VL sequence of antibody AL2p-2 or ofSEQ ID NO: 92, including post-translational modifications of thatsequence. In a particular embodiment, the VL comprises one, two or threeHVRs selected from: (a) the HVR-L1 amino acid sequence of antibodyAL2p-2, (b) the HVR-L2 amino acid sequence of antibody AL2p-2, and (c)the HVR-L3 amino acid sequence of antibody AL2p-2.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-3 or to the amino acid sequence of SEQ ID NO:29; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-3 or to the amino acid sequence of SEQ ID NO:92. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-3 or to the amino acid sequence of SEQ ID NO:29, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-3. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-3 or to the amino acid sequence of SEQ ID NO: 92, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-3. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-3 or to the amino acid sequence of SEQ ID NO:29 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-3 or the amino acid sequenceof SEQ ID NO: 29. In certain embodiments, a total of 1 to 5 amino acidshave been substituted, inserted and/or deleted in the heavy chainvariable domain amino acid sequence of antibody AL2p-3 or the amino acidsequence of SEQ ID NO: 29. In certain embodiments, substitutions,insertions, or deletions occur in regions outside the HVRs (i.e., in theFR regions). In some embodiments, the substitutions, insertions, ordeletions occur in in the FR regions. Optionally, the anti-TREM2antibody comprises the VH sequence of antibody AL2p-3 or of SEQ ID NO:29, including post-translational modifications of that sequence. In aparticular embodiment, the VH comprises one, two or three HVRs selectedfrom: (a) the HVR-H1 amino acid sequence of antibody AL2p-3, (b) theHVR-H2 amino acid sequence of antibody AL2p-3, and (c) the HVR-H3 aminoacid sequence of antibody AL2p-3. In some embodiments, anti-TREM2antibodies of the present disclosure comprise a light chain variabledomain (VL) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a light chain variabledomain amino acid sequence of antibody AL2p-3 or to the amino acidsequence of SEQ ID NO: 92 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the lightchain variable domain amino acid sequence of antibody AL2p-3 or theamino acid sequence of SEQ ID NO: 92. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in thelight chain variable domain amino acid sequence of antibody AL2p-3 orthe amino acid sequence of SEQ ID NO: 92. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VL sequence of antibody AL2p-3 or ofSEQ ID NO: 92, including post-translational modifications of thatsequence. In a particular embodiment, the VL comprises one, two or threeHVRs selected from: (a) the HVR-L1 amino acid sequence of antibodyAL2p-3, (b) the HVR-L2 amino acid sequence of antibody AL2p-3, and (c)the HVR-L3 amino acid sequence of antibody AL2p-3.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-4 or to the amino acid sequence of SEQ ID NO:30; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-4 or to the amino acid sequence of SEQ ID NO:92. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-4 or to the amino acid sequence of SEQ ID NO:30, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-4. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-4 or to the amino acid sequence of SEQ ID NO: 92, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-4. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-4 or to the amino acid sequence of SEQ ID NO:30 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-4 or the amino acid sequenceof SEQ ID NO: 30. In certain embodiments, a total of 1 to 5 amino acidshave been substituted, inserted and/or deleted in the heavy chainvariable domain amino acid sequence of antibody AL2p-4 or the amino acidsequence of SEQ ID NO: 30. In certain embodiments, substitutions,insertions, or deletions occur in regions outside the HVRs (i.e., in theFR regions). In some embodiments, the substitutions, insertions, ordeletions occur in in the FR regions. Optionally, the anti-TREM2antibody comprises the VH sequence of antibody AL2p-4 or of SEQ ID NO:30, including post-translational modifications of that sequence. In aparticular embodiment, the VH comprises one, two or three HVRs selectedfrom: (a) the HVR-H1 amino acid sequence of antibody AL2p-4, (b) theHVR-H2 amino acid sequence of antibody AL2p-4, and (c) the HVR-H3 aminoacid sequence of antibody AL2p-4. In some embodiments, anti-TREM2antibodies of the present disclosure comprise a light chain variabledomain (VL) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a light chain variabledomain amino acid sequence of antibody AL2p-4 or to the amino acidsequence of SEQ ID NO: 92 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the lightchain variable domain amino acid sequence of antibody AL2p-4 or theamino acid sequence of SEQ ID NO: 92. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in thelight chain variable domain amino acid sequence of antibody AL2p-4 orthe amino acid sequence of SEQ ID NO: 92. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VL sequence of antibody AL2p-4 or ofSEQ ID NO: 92, including post-translational modifications of thatsequence. In a particular embodiment, the VL comprises one, two or threeHVRs selected from: (a) the HVR-L1 amino acid sequence of antibodyAL2p-4, (b) the HVR-L2 amino acid sequence of antibody AL2p-4, and (c)the HVR-L3 amino acid sequence of antibody AL2p-4.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-7 or to the amino acid sequence of SEQ ID NO:31; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-7 or to the amino acid sequence of SEQ ID NO:95. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-7 or to the amino acid sequence of SEQ ID NO:31, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-7. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-7 or to the amino acid sequence of SEQ ID NO: 95, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-7. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-7 or to the amino acid sequence of SEQ ID NO:31 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-7 or the amino acid sequenceof SEQ ID NO: 31. In certain embodiments, a total of 1 to 5 amino acidshave been substituted, inserted and/or deleted in the heavy chainvariable domain amino acid sequence of antibody AL2p-7 or the amino acidsequence of SEQ ID NO: 31. In certain embodiments, substitutions,insertions, or deletions occur in regions outside the HVRs (i.e., in theFR regions). In some embodiments, the substitutions, insertions, ordeletions occur in in the FR regions. Optionally, the anti-TREM2antibody comprises the VH sequence of antibody AL2p-7 or of SEQ ID NO:31, including post-translational modifications of that sequence. In aparticular embodiment, the VH comprises one, two or three HVRs selectedfrom: (a) the HVR-H1 amino acid sequence of antibody AL2p-7, (b) theHVR-H2 amino acid sequence of antibody AL2p-7, and (c) the HVR-H3 aminoacid sequence of antibody AL2p-7. In some embodiments, anti-TREM2antibodies of the present disclosure comprise a light chain variabledomain (VL) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a light chain variabledomain amino acid sequence of antibody AL2p-7 or to the amino acidsequence of SEQ ID NO: 95 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the lightchain variable domain amino acid sequence of antibody AL2p-7 or theamino acid sequence of SEQ ID NO: 95. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in thelight chain variable domain amino acid sequence of antibody AL2p-7 orthe amino acid sequence of SEQ ID NO: 95. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VL sequence of antibody AL2p-7 or ofSEQ ID NO: 95, including post-translational modifications of thatsequence. In a particular embodiment, the VL comprises one, two or threeHVRs selected from: (a) the HVR-L1 amino acid sequence of antibodyAL2p-7, (b) the HVR-L2 amino acid sequence of antibody AL2p-7, and (c)the HVR-L3 amino acid sequence of antibody AL2p-7.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-8 or to the amino acid sequence of SEQ ID NO:32; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-8 or to the amino acid sequence of SEQ ID NO:95. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-8 or to the amino acid sequence of SEQ ID NO:32, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-8. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-8 or to the amino acid sequence of SEQ ID NO: 95, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-8. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-8 or to the amino acid sequence of SEQ ID NO:32 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-8 or the amino acid sequenceof SEQ ID NO: 32. In certain embodiments, a total of 1 to 5 amino acidshave been substituted, inserted and/or deleted in the heavy chainvariable domain amino acid sequence of antibody AL2p-8 or the amino acidsequence of SEQ ID NO: 32. In certain embodiments, substitutions,insertions, or deletions occur in regions outside the HVRs (i.e., in theFR regions). In some embodiments, the substitutions, insertions, ordeletions occur in in the FR regions. Optionally, the anti-TREM2antibody comprises the VH sequence of antibody AL2p-8 or of SEQ ID NO:32, including post-translational modifications of that sequence. In aparticular embodiment, the VH comprises one, two or three HVRs selectedfrom: (a) the HVR-H1 amino acid sequence of antibody AL2p-8, (b) theHVR-H2 amino acid sequence of antibody AL2p-8, and (c) the HVR-H3 aminoacid sequence of antibody AL2p-8. In some embodiments, anti-TREM2antibodies of the present disclosure comprise a light chain variabledomain (VL) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a light chain variabledomain amino acid sequence of antibody AL2p-8 or to the amino acidsequence of SEQ ID NO: 95 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the lightchain variable domain amino acid sequence of antibody AL2p-8 or theamino acid sequence of SEQ ID NO: 95. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in thelight chain variable domain amino acid sequence of antibody AL2p-8 orthe amino acid sequence of SEQ ID NO: 95. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VL sequence of antibody AL2p-8 or ofSEQ ID NO: 95, including post-translational modifications of thatsequence. In a particular embodiment, the VL comprises one, two or threeHVRs selected from: (a) the HVR-L1 amino acid sequence of antibodyAL2p-8, (b) the HVR-L2 amino acid sequence of antibody AL2p-8, and (c)the HVR-L3 amino acid sequence of antibody AL2p-8.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-9 or to the amino acid sequence of SEQ ID NO:33; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-9 or to the amino acid sequence of SEQ ID NO:96. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-9 or to the amino acid sequence of SEQ ID NO:33, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-9. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-9 or to the amino acid sequence of SEQ ID NO: 96, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-9. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-9 or to the amino acid sequence of SEQ ID NO:33 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-9 or the amino acid sequenceof SEQ ID NO: 33. In certain embodiments, a total of 1 to 5 amino acidshave been substituted, inserted and/or deleted in the heavy chainvariable domain amino acid sequence of antibody AL2p-9 or the amino acidsequence of SEQ ID NO: 33. In certain embodiments, substitutions,insertions, or deletions occur in regions outside the HVRs (i.e., in theFR regions). In some embodiments, the substitutions, insertions, ordeletions occur in in the FR regions. Optionally, the anti-TREM2antibody comprises the VH sequence of antibody AL2p-9 or of SEQ ID NO:33, including post-translational modifications of that sequence. In aparticular embodiment, the VH comprises one, two or three HVRs selectedfrom: (a) the HVR-H1 amino acid sequence of antibody AL2p-9, (b) theHVR-H2 amino acid sequence of antibody AL2p-9, and (c) the HVR-H3 aminoacid sequence of antibody AL2p-9. In some embodiments, anti-TREM2antibodies of the present disclosure comprise a light chain variabledomain (VL) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a light chain variabledomain amino acid sequence of antibody AL2p-9 or to the amino acidsequence of SEQ ID NO: 96 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the lightchain variable domain amino acid sequence of antibody AL2p-9 or theamino acid sequence of SEQ ID NO: 96. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in thelight chain variable domain amino acid sequence of antibody AL2p-9 orthe amino acid sequence of SEQ ID NO: 96. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VL sequence of antibody AL2p-9 or ofSEQ ID NO: 96, including post-translational modifications of thatsequence. In a particular embodiment, the VL comprises one, two or threeHVRs selected from: (a) the HVR-L1 amino acid sequence of antibodyAL2p-9, (b) the HVR-L2 amino acid sequence of antibody AL2p-9, and (c)the HVR-L3 amino acid sequence of antibody AL2p-9.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-10 or to the amino acid sequence of SEQ ID NO:34; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-10 or to the amino acid sequence of SEQ ID NO:97. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-10 or to the amino acid sequence of SEQ ID NO:34, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-10. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-10 or to the amino acid sequence of SEQ ID NO: 97, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-10. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-10 or to the amino acid sequence of SEQ ID NO:34 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-10 or the amino acidsequence of SEQ ID NO: 34. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-10 or theamino acid sequence of SEQ ID NO: 34. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-10 or ofSEQ ID NO: 34, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-10, (b) the HVR-H2 amino acid sequence of antibody AL2p-10, and (c)the HVR-H3 amino acid sequence of antibody AL2p-10. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-10 or to the aminoacid sequence of SEQ ID NO: 97 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-10 or the amino acid sequence of SEQ ID NO: 97. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-10 or the amino acid sequence of SEQ ID NO:97. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-10 or of SEQ ID NO: 97, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-10, (b) the HVR-L2 aminoacid sequence of antibody AL2p-10, and (c) the HVR-L3 amino acidsequence of antibody AL2p-10.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-11 or to the amino acid sequence of SEQ ID NO:35; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-11 or to the amino acid sequence of SEQ ID NO:98. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-11 or to the amino acid sequence of SEQ ID NO:35, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-11. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-11 or to the amino acid sequence of SEQ ID NO: 98, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-11. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-11 or to the amino acid sequence of SEQ ID NO:35 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-11 or the amino acidsequence of SEQ ID NO: 35. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-11 or theamino acid sequence of SEQ ID NO: 35. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-11 or ofSEQ ID NO: 35, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-11, (b) the HVR-H2 amino acid sequence of antibody AL2p-11, and (c)the HVR-H3 amino acid sequence of antibody AL2p-11. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-11 or to the aminoacid sequence of SEQ ID NO: 98 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-11 or the amino acid sequence of SEQ ID NO: 98. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-11 or the amino acid sequence of SEQ ID NO:98. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-11 or of SEQ ID NO: 98, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-11, (b) the HVR-L2 aminoacid sequence of antibody AL2p-11, and (c) the HVR-L3 amino acidsequence of antibody AL2p-11.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-12 or to the amino acid sequence of SEQ ID NO:36; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-12 or to the amino acid sequence of SEQ ID NO:97. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-12 or to the amino acid sequence of SEQ ID NO:36, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-12. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-12 or to the amino acid sequence of SEQ ID NO: 97, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-12. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-12 or to the amino acid sequence of SEQ ID NO:36 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-12 or the amino acidsequence of SEQ ID NO: 36. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-12 or theamino acid sequence of SEQ ID NO: 36. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-12 or ofSEQ ID NO: 36, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-12, (b) the HVR-H2 amino acid sequence of antibody AL2p-12, and (c)the HVR-H3 amino acid sequence of antibody AL2p-12. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-12 or to the aminoacid sequence of SEQ ID NO: 97 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-12 or the amino acid sequence of SEQ ID NO: 97. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-12 or the amino acid sequence of SEQ ID NO:97. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-12 or of SEQ ID NO: 97, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-12, (b) the HVR-L2 aminoacid sequence of antibody AL2p-12, and (c) the HVR-L3 amino acidsequence of antibody AL2p-12.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-13 or to the amino acid sequence of SEQ ID NO:37; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-13 or to the amino acid sequence of SEQ ID NO:95. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-13 or to the amino acid sequence of SEQ ID NO:37, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-13. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-13 or to the amino acid sequence of SEQ ID NO: 95, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-13. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-13 or to the amino acid sequence of SEQ ID NO:37 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-13 or the amino acidsequence of SEQ ID NO: 37. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-13 or theamino acid sequence of SEQ ID NO: 37. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-13 or ofSEQ ID NO: 37, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-13, (b) the HVR-H2 amino acid sequence of antibody AL2p-13, and (c)the HVR-H3 amino acid sequence of antibody AL2p-13. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-13 or to the aminoacid sequence of SEQ ID NO: 95 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-13 or the amino acid sequence of SEQ ID NO: 95. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-13 or the amino acid sequence of SEQ ID NO:95. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-13 or of SEQ ID NO: 95, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-13, (b) the HVR-L2 aminoacid sequence of antibody AL2p-13, and (c) the HVR-L3 amino acidsequence of antibody AL2p-13.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-14 or to the amino acid sequence of SEQ ID NO:38; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-14 or to the amino acid sequence of SEQ ID NO:99. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-14 or to the amino acid sequence of SEQ ID NO:38, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-14. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-14 or to the amino acid sequence of SEQ ID NO: 99, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-14. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-14 or to the amino acid sequence of SEQ ID NO:38 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-14 or the amino acidsequence of SEQ ID NO: 38. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-14 or theamino acid sequence of SEQ ID NO: 38. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-14 or ofSEQ ID NO: 38, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-14, (b) the HVR-H2 amino acid sequence of antibody AL2p-14, and (c)the HVR-H3 amino acid sequence of antibody AL2p-14. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-14 or to the aminoacid sequence of SEQ ID NO: 99 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-14 or the amino acid sequence of SEQ ID NO: 99. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-14 or the amino acid sequence of SEQ ID NO:99. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-14 or of SEQ ID NO: 99, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-14, (b) the HVR-L2 aminoacid sequence of antibody AL2p-14, and (c) the HVR-L3 amino acidsequence of antibody AL2p-14.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-15 or to the amino acid sequence of SEQ ID NO:38; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-15 or to the amino acid sequence of SEQ ID NO:100. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-15 or to the amino acid sequence ofSEQ ID NO: 38, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-15. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-15 or to the amino acid sequence of SEQ ID NO:100, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-15. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-15 or to the amino acidsequence of SEQ ID NO: 38 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-15 or theamino acid sequence of SEQ ID NO: 38. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-15 orthe amino acid sequence of SEQ ID NO: 38. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-15 or ofSEQ ID NO: 38, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-15, (b) the HVR-H2 amino acid sequence of antibody AL2p-15, and (c)the HVR-H3 amino acid sequence of antibody AL2p-15. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-15 or to the aminoacid sequence of SEQ ID NO: 100 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-15 or the amino acid sequence of SEQ ID NO: 100. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-15 or the amino acid sequence ofSEQ ID NO: 100. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-15 or of SEQ ID NO: 100, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-15, (b) the HVR-L2 aminoacid sequence of antibody AL2p-15, and (c) the HVR-L3 amino acidsequence of antibody AL2p-15.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-16 or to the amino acid sequence of SEQ ID NO:39; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-16 or to the amino acid sequence of SEQ ID NO:96. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-16 or to the amino acid sequence of SEQ ID NO:39, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-16. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-16 or to the amino acid sequence of SEQ ID NO: 96, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-16. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-16 or to the amino acid sequence of SEQ ID NO:39 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-16 or the amino acidsequence of SEQ ID NO: 39. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-16 or theamino acid sequence of SEQ ID NO: 39. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-16 or ofSEQ ID NO: 39, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-16, (b) the HVR-H2 amino acid sequence of antibody AL2p-16, and (c)the HVR-H3 amino acid sequence of antibody AL2p-16. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-16 or to the aminoacid sequence of SEQ ID NO: 96 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-16 or the amino acid sequence of SEQ ID NO: 96. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-16 or the amino acid sequence of SEQ ID NO:96. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-16 or of SEQ ID NO: 96, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-16, (b) the HVR-L2 aminoacid sequence of antibody AL2p-16, and (c) the HVR-L3 amino acidsequence of antibody AL2p-16.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-17 or to the amino acid sequence of SEQ ID NO:40; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-17 or to the amino acid sequence of SEQ ID NO:98. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-17 or to the amino acid sequence of SEQ ID NO:40, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-17. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-17 or to the amino acid sequence of SEQ ID NO: 98, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-17. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-17 or to the amino acid sequence of SEQ ID NO:40 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-17 or the amino acidsequence of SEQ ID NO: 40. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-17 or theamino acid sequence of SEQ ID NO: 40. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-17 or ofSEQ ID NO: 40, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-17, (b) the HVR-H2 amino acid sequence of antibody AL2p-17, and (c)the HVR-H3 amino acid sequence of antibody AL2p-17. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-17 or to the aminoacid sequence of SEQ ID NO: 98 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-17 or the amino acid sequence of SEQ ID NO: 98. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-17 or the amino acid sequence of SEQ ID NO:98. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-17 or of SEQ ID NO: 98, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-17, (b) the HVR-L2 aminoacid sequence of antibody AL2p-17, and (c) the HVR-L3 amino acidsequence of antibody AL2p-17.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-18 or to the amino acid sequence of SEQ ID NO:41; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-18 or to the amino acid sequence of SEQ ID NO:96. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-18 or to the amino acid sequence of SEQ ID NO:41, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-18. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-18 or to the amino acid sequence of SEQ ID NO: 96, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-18. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-18 or to the amino acid sequence of SEQ ID NO:41 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-18 or the amino acidsequence of SEQ ID NO: 41. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-18 or theamino acid sequence of SEQ ID NO: 41. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-18 or ofSEQ ID NO: 41, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-18, (b) the HVR-H2 amino acid sequence of antibody AL2p-18, and (c)the HVR-H3 amino acid sequence of antibody AL2p-18. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-18 or to the aminoacid sequence of SEQ ID NO: 96 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-18 or the amino acid sequence of SEQ ID NO: 96. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-18 or the amino acid sequence of SEQ ID NO:96. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-18 or of SEQ ID NO: 96, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-18, (b) the HVR-L2 aminoacid sequence of antibody AL2p-18, and (c) the HVR-L3 amino acidsequence of antibody AL2p-18.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-19 or to the amino acid sequence of SEQ ID NO:42; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-19 or to the amino acid sequence of SEQ ID NO:98. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-19 or to the amino acid sequence of SEQ ID NO:42, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-19. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-19 or to the amino acid sequence of SEQ ID NO: 98, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-19. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-19 or to the amino acid sequence of SEQ ID NO:42 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-19 or the amino acidsequence of SEQ ID NO: 42. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-19 or theamino acid sequence of SEQ ID NO: 42. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-19 or ofSEQ ID NO: 42, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-19, (b) the HVR-H2 amino acid sequence of antibody AL2p-19, and (c)the HVR-H3 amino acid sequence of antibody AL2p-19. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-19 or to the aminoacid sequence of SEQ ID NO: 98 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-19 or the amino acid sequence of SEQ ID NO: 98. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-19 or the amino acid sequence of SEQ ID NO:98. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-19 or of SEQ ID NO: 98, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-19, (b) the HVR-L2 aminoacid sequence of antibody AL2p-19, and (c) the HVR-L3 amino acidsequence of antibody AL2p-19.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-20 or to the amino acid sequence of SEQ ID NO:42; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-20 or to the amino acid sequence of SEQ ID NO:96. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-20 or to the amino acid sequence of SEQ ID NO:42, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-20. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-20 or to the amino acid sequence of SEQ ID NO: 96, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-20. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-20 or to the amino acid sequence of SEQ ID NO:42 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-20 or the amino acidsequence of SEQ ID NO: 42. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-20 or theamino acid sequence of SEQ ID NO: 42. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-20 or ofSEQ ID NO: 42, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-20, (b) the HVR-H2 amino acid sequence of antibody AL2p-20, and (c)the HVR-H3 amino acid sequence of antibody AL2p-20. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-20 or to the aminoacid sequence of SEQ ID NO: 96 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-20 or the amino acid sequence of SEQ ID NO: 96. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-20 or the amino acid sequence of SEQ ID NO:96. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-20 or of SEQ ID NO: 96, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-20, (b) the HVR-L2 aminoacid sequence of antibody AL2p-20, and (c) the HVR-L3 amino acidsequence of antibody AL2p-20.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-21 or to the amino acid sequence of SEQ ID NO:43; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-21 or to the amino acid sequence of SEQ ID NO:100. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-21 or to the amino acid sequence ofSEQ ID NO: 43, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-21. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-21 or to the amino acid sequence of SEQ ID NO:100, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-21. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-21 or to the amino acidsequence of SEQ ID NO: 43 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-21 or theamino acid sequence of SEQ ID NO: 43. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-21 orthe amino acid sequence of SEQ ID NO: 43. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-21 or ofSEQ ID NO: 43, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-21, (b) the HVR-H2 amino acid sequence of antibody AL2p-21, and (c)the HVR-H3 amino acid sequence of antibody AL2p-21. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-21 or to the aminoacid sequence of SEQ ID NO: 100 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-21 or the amino acid sequence of SEQ ID NO: 100. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-21 or the amino acid sequence ofSEQ ID NO: 100. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-21 or of SEQ ID NO: 100, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-21, (b) the HVR-L2 aminoacid sequence of antibody AL2p-21, and (c) the HVR-L3 amino acidsequence of antibody AL2p-21.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-22 or to the amino acid sequence of SEQ ID NO:44; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-22 or to the amino acid sequence of SEQ ID NO:101. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-22 or to the amino acid sequence ofSEQ ID NO: 44, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-22. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-22 or to the amino acid sequence of SEQ ID NO:101, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-22. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-22 or to the amino acidsequence of SEQ ID NO: 44 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-22 or theamino acid sequence of SEQ ID NO: 44. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-22 orthe amino acid sequence of SEQ ID NO: 44. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-22 or ofSEQ ID NO: 44, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-22, (b) the HVR-H2 amino acid sequence of antibody AL2p-22, and (c)the HVR-H3 amino acid sequence of antibody AL2p-22. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-22 or to the aminoacid sequence of SEQ ID NO: 101 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-22 or the amino acid sequence of SEQ ID NO: 101. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-22 or the amino acid sequence ofSEQ ID NO: 101. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-22 or of SEQ ID NO: 101, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-22, (b) the HVR-L2 aminoacid sequence of antibody AL2p-22, and (c) the HVR-L3 amino acidsequence of antibody AL2p-22.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-23 or to the amino acid sequence of SEQ ID NO:45; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-23 or to the amino acid sequence of SEQ ID NO:96. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-23 or to the amino acid sequence of SEQ ID NO:45, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-23. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-23 or to the amino acid sequence of SEQ ID NO: 96, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-23. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-23 or to the amino acid sequence of SEQ ID NO:45 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-23 or the amino acidsequence of SEQ ID NO: 45. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-23 or theamino acid sequence of SEQ ID NO: 45. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-23 or ofSEQ ID NO: 45, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-23, (b) the HVR-H2 amino acid sequence of antibody AL2p-23, and (c)the HVR-H3 amino acid sequence of antibody AL2p-23. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-23 or to the aminoacid sequence of SEQ ID NO: 96 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-23 or the amino acid sequence of SEQ ID NO: 96. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-23 or the amino acid sequence of SEQ ID NO:96. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-23 or of SEQ ID NO: 96, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-23, (b) the HVR-L2 aminoacid sequence of antibody AL2p-23, and (c) the HVR-L3 amino acidsequence of antibody AL2p-23.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-24 or to the amino acid sequence of SEQ ID NO:46; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-24 or to the amino acid sequence of SEQ ID NO:99. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-24 or to the amino acid sequence of SEQ ID NO:46, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-24. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-24 or to the amino acid sequence of SEQ ID NO: 99, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-24. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-24 or to the amino acid sequence of SEQ ID NO:46 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-24 or the amino acidsequence of SEQ ID NO: 46. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-24 or theamino acid sequence of SEQ ID NO: 46. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-24 or ofSEQ ID NO: 46, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-24, (b) the HVR-H2 amino acid sequence of antibody AL2p-24, and (c)the HVR-H3 amino acid sequence of antibody AL2p-24. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-24 or to the aminoacid sequence of SEQ ID NO: 99 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-24 or the amino acid sequence of SEQ ID NO: 99. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-24 or the amino acid sequence of SEQ ID NO:99. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-24 or of SEQ ID NO: 99, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-24, (b) the HVR-L2 aminoacid sequence of antibody AL2p-24, and (c) the HVR-L3 amino acidsequence of antibody AL2p-24.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-25 or to the amino acid sequence of SEQ ID NO:47; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-25 or to the amino acid sequence of SEQ ID NO:96. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-25 or to the amino acid sequence of SEQ ID NO:47, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-25. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-25 or to the amino acid sequence of SEQ ID NO: 96, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-25. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-25 or to the amino acid sequence of SEQ ID NO:47 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-25 or the amino acidsequence of SEQ ID NO: 47. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-25 or theamino acid sequence of SEQ ID NO: 47. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-25 or ofSEQ ID NO: 47, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-25, (b) the HVR-H2 amino acid sequence of antibody AL2p-25, and (c)the HVR-H3 amino acid sequence of antibody AL2p-25. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-25 or to the aminoacid sequence of SEQ ID NO: 96 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-25 or the amino acid sequence of SEQ ID NO: 96. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-25 or the amino acid sequence of SEQ ID NO:96. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-25 or of SEQ ID NO: 96, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-25, (b) the HVR-L2 aminoacid sequence of antibody AL2p-25, and (c) the HVR-L3 amino acidsequence of antibody AL2p-25.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-26 or to the amino acid sequence of SEQ ID NO:48; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-26 or to the amino acid sequence of SEQ ID NO:95. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-26 or to the amino acid sequence of SEQ ID NO:48, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-26. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-26 or to the amino acid sequence of SEQ ID NO: 95, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-26. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-26 or to the amino acid sequence of SEQ ID NO:48 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-26 or the amino acidsequence of SEQ ID NO: 48. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-26 or theamino acid sequence of SEQ ID NO: 48. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-26 or ofSEQ ID NO: 48, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-26, (b) the HVR-H2 amino acid sequence of antibody AL2p-26, and (c)the HVR-H3 amino acid sequence of antibody AL2p-26. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-26 or to the aminoacid sequence of SEQ ID NO: 95 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-26 or the amino acid sequence of SEQ ID NO: 95. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-26 or the amino acid sequence of SEQ ID NO:95. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-26 or of SEQ ID NO: 95, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-26, (b) the HVR-L2 aminoacid sequence of antibody AL2p-26, and (c) the HVR-L3 amino acidsequence of antibody AL2p-26.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-27 or to the amino acid sequence of SEQ ID NO:49; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-27 or to the amino acid sequence of SEQ ID NO:102. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-27 or to the amino acid sequence ofSEQ ID NO: 49, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-27. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-27 or to the amino acid sequence of SEQ ID NO:102, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-27. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-27 or to the amino acidsequence of SEQ ID NO: 49 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-27 or theamino acid sequence of SEQ ID NO: 49. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-27 orthe amino acid sequence of SEQ ID NO: 49. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-27 or ofSEQ ID NO: 49, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-27, (b) the HVR-H2 amino acid sequence of antibody AL2p-27, and (c)the HVR-H3 amino acid sequence of antibody AL2p-27. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-27 or to the aminoacid sequence of SEQ ID NO: 102 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-27 or the amino acid sequence of SEQ ID NO: 102. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-27 or the amino acid sequence ofSEQ ID NO: 102. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-27 or of SEQ ID NO: 102, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-27, (b) the HVR-L2 aminoacid sequence of antibody AL2p-27, and (c) the HVR-L3 amino acidsequence of antibody AL2p-27.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-28 or to the amino acid sequence of SEQ ID NO:50; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-28 or to the amino acid sequence of SEQ ID NO:96. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-28 or to the amino acid sequence of SEQ ID NO:50, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-28. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-28 or to the amino acid sequence of SEQ ID NO: 96, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-28. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-28 or to the amino acid sequence of SEQ ID NO:50 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-28 or the amino acidsequence of SEQ ID NO: 50. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-28 or theamino acid sequence of SEQ ID NO: 50. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-28 or ofSEQ ID NO: 50, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-28, (b) the HVR-H2 amino acid sequence of antibody AL2p-28, and (c)the HVR-H3 amino acid sequence of antibody AL2p-28. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-28 or to the aminoacid sequence of SEQ ID NO: 96 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-28 or the amino acid sequence of SEQ ID NO: 96. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-28 or the amino acid sequence of SEQ ID NO:96. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-28 or of SEQ ID NO: 96, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-28, (b) the HVR-L2 aminoacid sequence of antibody AL2p-28, and (c) the HVR-L3 amino acidsequence of antibody AL2p-28.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-29 or to the amino acid sequence of SEQ ID NO:51; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-29 or to the amino acid sequence of SEQ ID NO:99. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-29 or to the amino acid sequence of SEQ ID NO:51, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-29. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-29 or to the amino acid sequence of SEQ ID NO: 99, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-29. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-29 or to the amino acid sequence of SEQ ID NO:51 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-29 or the amino acidsequence of SEQ ID NO: 51. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-29 or theamino acid sequence of SEQ ID NO: 51. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-29 or ofSEQ ID NO: 51, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-29, (b) the HVR-H2 amino acid sequence of antibody AL2p-29, and (c)the HVR-H3 amino acid sequence of antibody AL2p-29. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-29 or to the aminoacid sequence of SEQ ID NO: 99 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-29 or the amino acid sequence of SEQ ID NO: 99. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-29 or the amino acid sequence of SEQ ID NO:99. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-29 or of SEQ ID NO: 99, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-29, (b) the HVR-L2 aminoacid sequence of antibody AL2p-29, and (c) the HVR-L3 amino acidsequence of antibody AL2p-29.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-30 or to the amino acid sequence of SEQ ID NO:52; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-30 or to the amino acid sequence of SEQ ID NO:100. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-30 or to the amino acid sequence ofSEQ ID NO: 52, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-30. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-30 or to the amino acid sequence of SEQ ID NO:100, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-30. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-30 or to the amino acidsequence of SEQ ID NO: 52 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-30 or theamino acid sequence of SEQ ID NO: 52. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-30 orthe amino acid sequence of SEQ ID NO: 52. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-30 or ofSEQ ID NO: 52, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-30, (b) the HVR-H2 amino acid sequence of antibody AL2p-30, and (c)the HVR-H3 amino acid sequence of antibody AL2p-30. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-30 or to the aminoacid sequence of SEQ ID NO: 100 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-30 or the amino acid sequence of SEQ ID NO: 100. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-30 or the amino acid sequence ofSEQ ID NO: 100. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-30 or of SEQ ID NO: 100, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-30, (b) the HVR-L2 aminoacid sequence of antibody AL2p-30, and (c) the HVR-L3 amino acidsequence of antibody AL2p-30.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-31 or to the amino acid sequence of SEQ ID NO:53; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-31 or to the amino acid sequence of SEQ ID NO:97. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-31 or to the amino acid sequence of SEQ ID NO:53, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-31. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-31 or to the amino acid sequence of SEQ ID NO: 97, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-31. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-31 or to the amino acid sequence of SEQ ID NO:53 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-31 or the amino acidsequence of SEQ ID NO: 53. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-31 or theamino acid sequence of SEQ ID NO: 53. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-31 or ofSEQ ID NO: 53, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-31, (b) the HVR-H2 amino acid sequence of antibody AL2p-31, and (c)the HVR-H3 amino acid sequence of antibody AL2p-31. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-31 or to the aminoacid sequence of SEQ ID NO: 97 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-31 or the amino acid sequence of SEQ ID NO: 97. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-31 or the amino acid sequence of SEQ ID NO:97. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-31 or of SEQ ID NO: 97, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-31, (b) the HVR-L2 aminoacid sequence of antibody AL2p-31, and (c) the HVR-L3 amino acidsequence of antibody AL2p-31.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-32 or to the amino acid sequence of SEQ ID NO:54; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-32 or to the amino acid sequence of SEQ ID NO:97. In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a heavy chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-32 or to the amino acid sequence of SEQ ID NO:54, wherein the heavy chain variable domain comprises the HVR-H1,HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-32. In someembodiments, anti-TREM2 antibodies of the present disclosure comprise alight chain variable domain comprising an amino acid sequence with atleast 85%, at least 86%, at least 87%, at least 88%, at least 89%, atleast 90%, at least 91%, at least 92%, at least 93%, at least 94%, atleast 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% identity to a light chain variable domain amino acid sequence ofantibody AL2p-32 or to the amino acid sequence of SEQ ID NO: 97, whereinthe light chain variable domain comprises the HVR-L1, HVR-L2, and HVR-L3amino acid sequences of antibody AL2p-32. In some embodiments, theanti-TREM2 antibody comprises a heavy chain variable domain (VH)sequence having at least 85%, at least 86%, at least 87%, at least 88%,at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-32 or to the amino acid sequence of SEQ ID NO:54 and contains substitutions (e.g., conservative substitutions,insertions, or deletions relative to the reference sequence), but theanti-TREM2 antibody comprising that sequence retains the ability to bindto TREM2. In certain embodiments, a total of 1 to 10 amino acids havebeen substituted, inserted, and/or deleted in the heavy chain variabledomain amino acid sequence of antibody AL2p-32 or the amino acidsequence of SEQ ID NO: 54. In certain embodiments, a total of 1 to 5amino acids have been substituted, inserted and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-32 or theamino acid sequence of SEQ ID NO: 54. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-32 or ofSEQ ID NO: 54, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-32, (b) the HVR-H2 amino acid sequence of antibody AL2p-32, and (c)the HVR-H3 amino acid sequence of antibody AL2p-32. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-32 or to the aminoacid sequence of SEQ ID NO: 97 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-32 or the amino acid sequence of SEQ ID NO: 97. In certainembodiments, a total of 1 to 5 amino acids have been substituted,inserted and/or deleted in the light chain variable domain amino acidsequence of antibody AL2p-32 or the amino acid sequence of SEQ ID NO:97. In certain embodiments, substitutions, insertions, or deletionsoccur in regions outside the HVRs (i.e., in the FR regions). In someembodiments, the substitutions, insertions, or deletions occur in in theFR regions. Optionally, the anti-TREM2 antibody comprises the VLsequence of antibody AL2p-32 or of SEQ ID NO: 97, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-32, (b) the HVR-L2 aminoacid sequence of antibody AL2p-32, and (c) the HVR-L3 amino acidsequence of antibody AL2p-32.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-33 or to the amino acid sequence of SEQ ID NO:55; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-33 or to the amino acid sequence of SEQ ID NO:103. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-33 or to the amino acid sequence ofSEQ ID NO: 55, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-33. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-33 or to the amino acid sequence of SEQ ID NO:103, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-33. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-33 or to the amino acidsequence of SEQ ID NO: 55 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-33 or theamino acid sequence of SEQ ID NO: 55. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-33 orthe amino acid sequence of SEQ ID NO: 55. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-33 or ofSEQ ID NO: 55, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-33, (b) the HVR-H2 amino acid sequence of antibody AL2p-33, and (c)the HVR-H3 amino acid sequence of antibody AL2p-33. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-33 or to the aminoacid sequence of SEQ ID NO: 103 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-33 or the amino acid sequence of SEQ ID NO: 103. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-33 or the amino acid sequence ofSEQ ID NO: 103. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-33 or of SEQ ID NO: 103, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-33, (b) the HVR-L2 aminoacid sequence of antibody AL2p-33, and (c) the HVR-L3 amino acidsequence of antibody AL2p-33.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-35 or to the amino acid sequence of SEQ ID NO:57; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-35 or to the amino acid sequence of SEQ ID NO:104. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-35 or to the amino acid sequence ofSEQ ID NO: 57, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-35. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-35 or to the amino acid sequence of SEQ ID NO:104, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-35. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-35 or to the amino acidsequence of SEQ ID NO: 57 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-35 or theamino acid sequence of SEQ ID NO: 57. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-35 orthe amino acid sequence of SEQ ID NO: 57. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-35 or ofSEQ ID NO: 57, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-35, (b) the HVR-H2 amino acid sequence of antibody AL2p-35, and (c)the HVR-H3 amino acid sequence of antibody AL2p-35. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-35 or to the aminoacid sequence of SEQ ID NO: 104 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-35 or the amino acid sequence of SEQ ID NO: 104. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-35 or the amino acid sequence ofSEQ ID NO: 104. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-35 or of SEQ ID NO: 104, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-35, (b) the HVR-L2 aminoacid sequence of antibody AL2p-35, and (c) the HVR-L3 amino acidsequence of antibody AL2p-35.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-36 or to the amino acid sequence of SEQ ID NO:58; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-36 or to the amino acid sequence of SEQ ID NO:104. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-36 or to the amino acid sequence ofSEQ ID NO: 58, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-36. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-36 or to the amino acid sequence of SEQ ID NO:104, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-36. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-36 or to the amino acidsequence of SEQ ID NO: 58 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-36 or theamino acid sequence of SEQ ID NO: 58. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-36 orthe amino acid sequence of SEQ ID NO: 58. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-36 or ofSEQ ID NO: 58, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-36, (b) the HVR-H2 amino acid sequence of antibody AL2p-36, and (c)the HVR-H3 amino acid sequence of antibody AL2p-36. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-36 or to the aminoacid sequence of SEQ ID NO: 104 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-36 or the amino acid sequence of SEQ ID NO: 104. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-36 or the amino acid sequence ofSEQ ID NO: 104. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-36 or of SEQ ID NO: 104, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-36, (b) the HVR-L2 aminoacid sequence of antibody AL2p-36, and (c) the HVR-L3 amino acidsequence of antibody AL2p-36.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-37 or to the amino acid sequence of SEQ ID NO:59; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-37 or to the amino acid sequence of SEQ ID NO:104. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-37 or to the amino acid sequence ofSEQ ID NO: 59, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-37. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-37 or to the amino acid sequence of SEQ ID NO:104, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-37. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-37 or to the amino acidsequence of SEQ ID NO: 59 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-37 or theamino acid sequence of SEQ ID NO: 59. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-37 orthe amino acid sequence of SEQ ID NO: 59. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-37 or ofSEQ ID NO: 59, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-37, (b) the HVR-H2 amino acid sequence of antibody AL2p-37, and (c)the HVR-H3 amino acid sequence of antibody AL2p-37. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-37 or to the aminoacid sequence of SEQ ID NO: 104 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-37 or the amino acid sequence of SEQ ID NO: 104. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-37 or the amino acid sequence ofSEQ ID NO: 104. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-37 or of SEQ ID NO: 104, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-37, (b) the HVR-L2 aminoacid sequence of antibody AL2p-37, and (c) the HVR-L3 amino acidsequence of antibody AL2p-37.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-38 or to the amino acid sequence of SEQ ID NO:60; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-38 or to the amino acid sequence of SEQ ID NO:105. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-38 or to the amino acid sequence ofSEQ ID NO: 60, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-38. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-38 or to the amino acid sequence of SEQ ID NO:105, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-38. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-38 or to the amino acidsequence of SEQ ID NO: 60 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-38 or theamino acid sequence of SEQ ID NO: 60. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-38 orthe amino acid sequence of SEQ ID NO: 60. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-38 or ofSEQ ID NO: 60, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-38, (b) the HVR-H2 amino acid sequence of antibody AL2p-38, and (c)the HVR-H3 amino acid sequence of antibody AL2p-38. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-38 or to the aminoacid sequence of SEQ ID NO: 105 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-38 or the amino acid sequence of SEQ ID NO: 105. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-38 or the amino acid sequence ofSEQ ID NO: 105. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-38 or of SEQ ID NO: 105, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-38, (b) the HVR-L2 aminoacid sequence of antibody AL2p-38, and (c) the HVR-L3 amino acidsequence of antibody AL2p-38.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-39 or to the amino acid sequence of SEQ ID NO:60; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-39 or to the amino acid sequence of SEQ ID NO:106. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-39 or to the amino acid sequence ofSEQ ID NO: 60, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-39. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-39 or to the amino acid sequence of SEQ ID NO:106, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-39. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-39 or to the amino acidsequence of SEQ ID NO: 60 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-39 or theamino acid sequence of SEQ ID NO: 60. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-39 orthe amino acid sequence of SEQ ID NO: 60. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-39 or ofSEQ ID NO: 60, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-39, (b) the HVR-H2 amino acid sequence of antibody AL2p-39, and (c)the HVR-H3 amino acid sequence of antibody AL2p-39. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-39 or to the aminoacid sequence of SEQ ID NO: 106 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-39 or the amino acid sequence of SEQ ID NO: 106. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-39 or the amino acid sequence ofSEQ ID NO: 106. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-39 or of SEQ ID NO: 106, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-39, (b) the HVR-L2 aminoacid sequence of antibody AL2p-39, and (c) the HVR-L3 amino acidsequence of antibody AL2p-39.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-40 or to the amino acid sequence of SEQ ID NO:60; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-40 or to the amino acid sequence of SEQ ID NO:107. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-40 or to the amino acid sequence ofSEQ ID NO: 60, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-40. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-40 or to the amino acid sequence of SEQ ID NO:107, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-40. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-40 or to the amino acidsequence of SEQ ID NO: 60 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-40 or theamino acid sequence of SEQ ID NO: 60. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-40 orthe amino acid sequence of SEQ ID NO: 60. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-40 or ofSEQ ID NO: 60, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-40, (b) the HVR-H2 amino acid sequence of antibody AL2p-40, and (c)the HVR-H3 amino acid sequence of antibody AL2p-40. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-40 or to the aminoacid sequence of SEQ ID NO: 107 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-40 or the amino acid sequence of SEQ ID NO: 107. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-40 or the amino acid sequence ofSEQ ID NO: 107. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-40 or of SEQ ID NO: 107, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-40, (b) the HVR-L2 aminoacid sequence of antibody AL2p-40, and (c) the HVR-L3 amino acidsequence of antibody AL2p-40.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-41 or to the amino acid sequence of SEQ ID NO:61; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-41 or to the amino acid sequence of SEQ ID NO:106. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-41 or to the amino acid sequence ofSEQ ID NO: 61, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-41. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-41 or to the amino acid sequence of SEQ ID NO:106, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-41. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-41 or to the amino acidsequence of SEQ ID NO: 61 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-41 or theamino acid sequence of SEQ ID NO: 61. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-41 orthe amino acid sequence of SEQ ID NO: 61. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-41 or ofSEQ ID NO: 61, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-41, (b) the HVR-H2 amino acid sequence of antibody AL2p-41, and (c)the HVR-H3 amino acid sequence of antibody AL2p-41. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-41 or to the aminoacid sequence of SEQ ID NO: 106 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-41 or the amino acid sequence of SEQ ID NO: 106. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-41 or the amino acid sequence ofSEQ ID NO: 106. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-41 or of SEQ ID NO: 106, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-41, (b) the HVR-L2 aminoacid sequence of antibody AL2p-41, and (c) the HVR-L3 amino acidsequence of antibody AL2p-41.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-42 or to the amino acid sequence of SEQ ID NO:61; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-42 or to the amino acid sequence of SEQ ID NO:107. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-42 or to the amino acid sequence ofSEQ ID NO: 61, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-42. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-42 or to the amino acid sequence of SEQ ID NO:107, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-42. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-42 or to the amino acidsequence of SEQ ID NO: 61 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-42 or theamino acid sequence of SEQ ID NO: 61. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-42 orthe amino acid sequence of SEQ ID NO: 61. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-42 or ofSEQ ID NO: 61, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-42, (b) the HVR-H2 amino acid sequence of antibody AL2p-42, and (c)the HVR-H3 amino acid sequence of antibody AL2p-42. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-42 or to the aminoacid sequence of SEQ ID NO: 107 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-42 or the amino acid sequence of SEQ ID NO: 107. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-42 or the amino acid sequence ofSEQ ID NO: 107. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-42 or of SEQ ID NO: 107, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-42, (b) the HVR-L2 aminoacid sequence of antibody AL2p-42, and (c) the HVR-L3 amino acidsequence of antibody AL2p-42.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-43 or to the amino acid sequence of SEQ ID NO:62; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-43 or to the amino acid sequence of SEQ ID NO:105. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-43 or to the amino acid sequence ofSEQ ID NO: 62, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-43. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-43 or to the amino acid sequence of SEQ ID NO:105, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-43. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-43 or to the amino acidsequence of SEQ ID NO: 62 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-43 or theamino acid sequence of SEQ ID NO: 62. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-43 orthe amino acid sequence of SEQ ID NO: 62. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-43 or ofSEQ ID NO: 62, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-43, (b) the HVR-H2 amino acid sequence of antibody AL2p-43, and (c)the HVR-H3 amino acid sequence of antibody AL2p-43. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-43 or to the aminoacid sequence of SEQ ID NO: 105 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-43 or the amino acid sequence of SEQ ID NO: 105. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-43 or the amino acid sequence ofSEQ ID NO: 105. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-43 or of SEQ ID NO: 105, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-43, (b) the HVR-L2 aminoacid sequence of antibody AL2p-43, and (c) the HVR-L3 amino acidsequence of antibody AL2p-43.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-44 or to the amino acid sequence of SEQ ID NO:62; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-44 or to the amino acid sequence of SEQ ID NO:107. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-44 or to the amino acid sequence ofSEQ ID NO: 62, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-44. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-44 or to the amino acid sequence of SEQ ID NO:107, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-44. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-44 or to the amino acidsequence of SEQ ID NO: 62 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-44 or theamino acid sequence of SEQ ID NO: 62. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-44 orthe amino acid sequence of SEQ ID NO: 62. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-44 or ofSEQ ID NO: 62, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-44, (b) the HVR-H2 amino acid sequence of antibody AL2p-44, and (c)the HVR-H3 amino acid sequence of antibody AL2p-44. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-44 or to the aminoacid sequence of SEQ ID NO: 107 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-44 or the amino acid sequence of SEQ ID NO: 107. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-44 or the amino acid sequence ofSEQ ID NO: 107. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-44 or of SEQ ID NO: 107, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-44, (b) the HVR-L2 aminoacid sequence of antibody AL2p-44, and (c) the HVR-L3 amino acidsequence of antibody AL2p-44.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-45 or to the amino acid sequence of SEQ ID NO:63; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-45 or to the amino acid sequence of SEQ ID NO:108. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-45 or to the amino acid sequence ofSEQ ID NO: 63, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-45. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-45 or to the amino acid sequence of SEQ ID NO:108, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-45. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-45 or to the amino acidsequence of SEQ ID NO: 63 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-45 or theamino acid sequence of SEQ ID NO: 63. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-45 orthe amino acid sequence of SEQ ID NO: 63. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-45 or ofSEQ ID NO: 63, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-45, (b) the HVR-H2 amino acid sequence of antibody AL2p-45, and (c)the HVR-H3 amino acid sequence of antibody AL2p-45. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-45 or to the aminoacid sequence of SEQ ID NO: 108 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-45 or the amino acid sequence of SEQ ID NO: 108. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-45 or the amino acid sequence ofSEQ ID NO: 108. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-45 or of SEQ ID NO: 108, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-45, (b) the HVR-L2 aminoacid sequence of antibody AL2p-45, and (c) the HVR-L3 amino acidsequence of antibody AL2p-45.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-46 or to the amino acid sequence of SEQ ID NO:63; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-46 or to the amino acid sequence of SEQ ID NO:109. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-46 or to the amino acid sequence ofSEQ ID NO: 63, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-46. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-46 or to the amino acid sequence of SEQ ID NO:109, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-46. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-46 or to the amino acidsequence of SEQ ID NO: 63 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-46 or theamino acid sequence of SEQ ID NO: 63. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-46 orthe amino acid sequence of SEQ ID NO: 63. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-46 or ofSEQ ID NO: 63, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-46, (b) the HVR-H2 amino acid sequence of antibody AL2p-46, and (c)the HVR-H3 amino acid sequence of antibody AL2p-46. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-46 or to the aminoacid sequence of SEQ ID NO: 109 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-46 or the amino acid sequence of SEQ ID NO: 109. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-46 or the amino acid sequence ofSEQ ID NO: 109. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-46 or of SEQ ID NO: 109, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-46, (b) the HVR-L2 aminoacid sequence of antibody AL2p-46, and (c) the HVR-L3 amino acidsequence of antibody AL2p-46.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-47 or to the amino acid sequence of SEQ ID NO:64; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-47 or to the amino acid sequence of SEQ ID NO:108. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-47 or to the amino acid sequence ofSEQ ID NO: 64, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-47. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-47 or to the amino acid sequence of SEQ ID NO:108, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-47. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-47 or to the amino acidsequence of SEQ ID NO: 64 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-47 or theamino acid sequence of SEQ ID NO: 64. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-47 orthe amino acid sequence of SEQ ID NO: 64. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-47 or ofSEQ ID NO: 64, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-47, (b) the HVR-H2 amino acid sequence of antibody AL2p-47, and (c)the HVR-H3 amino acid sequence of antibody AL2p-47. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-47 or to the aminoacid sequence of SEQ ID NO: 108 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-47 or the amino acid sequence of SEQ ID NO: 108. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-47 or the amino acid sequence ofSEQ ID NO: 108. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-47 or of SEQ ID NO: 108, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-47, (b) the HVR-L2 aminoacid sequence of antibody AL2p-47, and (c) the HVR-L3 amino acidsequence of antibody AL2p-47.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-48 or to the amino acid sequence of SEQ ID NO:64; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-48 or to the amino acid sequence of SEQ ID NO:109. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-48 or to the amino acid sequence ofSEQ ID NO: 64, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-48. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-48 or to the amino acid sequence of SEQ ID NO:109, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-48. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-48 or to the amino acidsequence of SEQ ID NO: 64 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-48 or theamino acid sequence of SEQ ID NO: 64. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-48 orthe amino acid sequence of SEQ ID NO: 64. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-48 or ofSEQ ID NO: 64, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-48, (b) the HVR-H2 amino acid sequence of antibody AL2p-48, and (c)the HVR-H3 amino acid sequence of antibody AL2p-48. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-48 or to the aminoacid sequence of SEQ ID NO: 109 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-48 or the amino acid sequence of SEQ ID NO: 109. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-48 or the amino acid sequence ofSEQ ID NO: 109. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-48 or of SEQ ID NO: 109, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-48, (b) the HVR-L2 aminoacid sequence of antibody AL2p-48, and (c) the HVR-L3 amino acidsequence of antibody AL2p-48.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-49 or to the amino acid sequence of SEQ ID NO:65; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-49 or to the amino acid sequence of SEQ ID NO:109. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-49 or to the amino acid sequence ofSEQ ID NO: 65, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-49. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-49 or to the amino acid sequence of SEQ ID NO:109, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-49. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-49 or to the amino acidsequence of SEQ ID NO: 65 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-49 or theamino acid sequence of SEQ ID NO: 65. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-49 orthe amino acid sequence of SEQ ID NO: 65. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-49 or ofSEQ ID NO: 65, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-49, (b) the HVR-H2 amino acid sequence of antibody AL2p-49, and (c)the HVR-H3 amino acid sequence of antibody AL2p-49. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-49 or to the aminoacid sequence of SEQ ID NO: 109 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-49 or the amino acid sequence of SEQ ID NO: 109. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-49 or the amino acid sequence ofSEQ ID NO: 109. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-49 or of SEQ ID NO: 109, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-49, (b) the HVR-L2 aminoacid sequence of antibody AL2p-49, and (c) the HVR-L3 amino acidsequence of antibody AL2p-49.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-50 or to the amino acid sequence of SEQ ID NO:66; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-50 or to the amino acid sequence of SEQ ID NO:108. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-50 or to the amino acid sequence ofSEQ ID NO: 66, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-50. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-50 or to the amino acid sequence of SEQ ID NO:108, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-50. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-50 or to the amino acidsequence of SEQ ID NO: 66 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-50 or theamino acid sequence of SEQ ID NO: 66. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-50 orthe amino acid sequence of SEQ ID NO: 66. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-50 or ofSEQ ID NO: 66, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-50, (b) the HVR-H2 amino acid sequence of antibody AL2p-50, and (c)the HVR-H3 amino acid sequence of antibody AL2p-50. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-50 or to the aminoacid sequence of SEQ ID NO: 108 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-50 or the amino acid sequence of SEQ ID NO: 108. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-50 or the amino acid sequence ofSEQ ID NO: 108. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-50 or of SEQ ID NO: 108, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-50, (b) the HVR-L2 aminoacid sequence of antibody AL2p-50, and (c) the HVR-L3 amino acidsequence of antibody AL2p-50.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-51 or to the amino acid sequence of SEQ ID NO:66; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-51 or to the amino acid sequence of SEQ ID NO:109. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-51 or to the amino acid sequence ofSEQ ID NO: 66, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-51. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-51 or to the amino acid sequence of SEQ ID NO:109, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-51. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-51 or to the amino acidsequence of SEQ ID NO: 66 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-51 or theamino acid sequence of SEQ ID NO: 66. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-51 orthe amino acid sequence of SEQ ID NO: 66. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-51 or ofSEQ ID NO: 66, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-51, (b) the HVR-H2 amino acid sequence of antibody AL2p-51, and (c)the HVR-H3 amino acid sequence of antibody AL2p-51. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-51 or to the aminoacid sequence of SEQ ID NO: 109 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-51 or the amino acid sequence of SEQ ID NO: 109. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-51 or the amino acid sequence ofSEQ ID NO: 109. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-51 or of SEQ ID NO: 109, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-51, (b) the HVR-L2 aminoacid sequence of antibody AL2p-51, and (c) the HVR-L3 amino acidsequence of antibody AL2p-51.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-52 or to the amino acid sequence of SEQ ID NO:67; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-52 or to the amino acid sequence of SEQ ID NO:108. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-52 or to the amino acid sequence ofSEQ ID NO: 67, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-52. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-52 or to the amino acid sequence of SEQ ID NO:108, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-52. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-52 or to the amino acidsequence of SEQ ID NO: 67 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-52 or theamino acid sequence of SEQ ID NO: 67. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-52 orthe amino acid sequence of SEQ ID NO: 67. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-52 or ofSEQ ID NO: 67, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-52, (b) the HVR-H2 amino acid sequence of antibody AL2p-52, and (c)the HVR-H3 amino acid sequence of antibody AL2p-52. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-52 or to the aminoacid sequence of SEQ ID NO: 108 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-52 or the amino acid sequence of SEQ ID NO: 108. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-52 or the amino acid sequence ofSEQ ID NO: 108. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-52 or of SEQ ID NO: 108, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-52, (b) the HVR-L2 aminoacid sequence of antibody AL2p-52, and (c) the HVR-L3 amino acidsequence of antibody AL2p-52.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-53 or to the amino acid sequence of SEQ ID NO:67; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-53 or to the amino acid sequence of SEQ ID NO:109. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-53 or to the amino acid sequence ofSEQ ID NO: 67, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-53. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-53 or to the amino acid sequence of SEQ ID NO:109, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-53. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-53 or to the amino acidsequence of SEQ ID NO: 67 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-53 or theamino acid sequence of SEQ ID NO: 67. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-53 orthe amino acid sequence of SEQ ID NO: 67. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-53 or ofSEQ ID NO: 67, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-53, (b) the HVR-H2 amino acid sequence of antibody AL2p-53, and (c)the HVR-H3 amino acid sequence of antibody AL2p-53. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-53 or to the aminoacid sequence of SEQ ID NO: 109 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-53 or the amino acid sequence of SEQ ID NO: 109. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-53 or the amino acid sequence ofSEQ ID NO: 109. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-53 or of SEQ ID NO: 109, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-53, (b) the HVR-L2 aminoacid sequence of antibody AL2p-53, and (c) the HVR-L3 amino acidsequence of antibody AL2p-53.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-54 or to the amino acid sequence of SEQ ID NO:68; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-54 or to the amino acid sequence of SEQ ID NO:109. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-54 or to the amino acid sequence ofSEQ ID NO: 68, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-54. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-54 or to the amino acid sequence of SEQ ID NO:109, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-54. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-54 or to the amino acidsequence of SEQ ID NO: 68 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-54 or theamino acid sequence of SEQ ID NO: 68. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-54 orthe amino acid sequence of SEQ ID NO: 68. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-54 or ofSEQ ID NO: 68, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-54, (b) the HVR-H2 amino acid sequence of antibody AL2p-54, and (c)the HVR-H3 amino acid sequence of antibody AL2p-54. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-54 or to the aminoacid sequence of SEQ ID NO: 109 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-54 or the amino acid sequence of SEQ ID NO: 109. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-54 or the amino acid sequence ofSEQ ID NO: 109. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-54 or of SEQ ID NO: 109, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-54, (b) the HVR-L2 aminoacid sequence of antibody AL2p-54, and (c) the HVR-L3 amino acidsequence of antibody AL2p-54.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-55 or to the amino acid sequence of SEQ ID NO:69; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-55 or to the amino acid sequence of SEQ ID NO:108. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-55 or to the amino acid sequence ofSEQ ID NO: 69, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-55. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-55 or to the amino acid sequence of SEQ ID NO:108, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-55. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-55 or to the amino acidsequence of SEQ ID NO: 69 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-55 or theamino acid sequence of SEQ ID NO: 69. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-55 orthe amino acid sequence of SEQ ID NO: 69. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-55 or ofSEQ ID NO: 69, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-55, (b) the HVR-H2 amino acid sequence of antibody AL2p-55, and (c)the HVR-H3 amino acid sequence of antibody AL2p-55. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-55 or to the aminoacid sequence of SEQ ID NO: 108 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-55 or the amino acid sequence of SEQ ID NO: 108. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-55 or the amino acid sequence ofSEQ ID NO: 108. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-55 or of SEQ ID NO: 108, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-55, (b) the HVR-L2 aminoacid sequence of antibody AL2p-55, and (c) the HVR-L3 amino acidsequence of antibody AL2p-55.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-56 or to the amino acid sequence of SEQ ID NO:69; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-56 or to the amino acid sequence of SEQ ID NO:108. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-56 or to the amino acid sequence ofSEQ ID NO: 69, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-56. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-56 or to the amino acid sequence of SEQ ID NO:108, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-56. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-56 or to the amino acidsequence of SEQ ID NO: 69 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-56 or theamino acid sequence of SEQ ID NO: 69. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-56 orthe amino acid sequence of SEQ ID NO: 69. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-56 or ofSEQ ID NO: 69, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-56, (b) the HVR-H2 amino acid sequence of antibody AL2p-56, and (c)the HVR-H3 amino acid sequence of antibody AL2p-56. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-56 or to the aminoacid sequence of SEQ ID NO: 108 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-56 or the amino acid sequence of SEQ ID NO: 108. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-56 or the amino acid sequence ofSEQ ID NO: 108. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-56 or of SEQ ID NO: 108, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-56, (b) the HVR-L2 aminoacid sequence of antibody AL2p-56, and (c) the HVR-L3 amino acidsequence of antibody AL2p-56.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-57 or to the amino acid sequence of SEQ ID NO:69; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-57 or to the amino acid sequence of SEQ ID NO:109. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-57 or to the amino acid sequence ofSEQ ID NO: 69, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-57. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-57 or to the amino acid sequence of SEQ ID NO:109, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-57. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-57 or to the amino acidsequence of SEQ ID NO: 69 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-57 or theamino acid sequence of SEQ ID NO: 69. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-57 orthe amino acid sequence of SEQ ID NO: 69. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-57 or ofSEQ ID NO: 69, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-57, (b) the HVR-H2 amino acid sequence of antibody AL2p-57, and (c)the HVR-H3 amino acid sequence of antibody AL2p-57. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-57 or to the aminoacid sequence of SEQ ID NO: 109 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-57 or the amino acid sequence of SEQ ID NO: 109. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-57 or the amino acid sequence ofSEQ ID NO: 109. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-57 or of SEQ ID NO: 109, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-57, (b) the HVR-L2 aminoacid sequence of antibody AL2p-57, and (c) the HVR-L3 amino acidsequence of antibody AL2p-57.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-58 or to the amino acid sequence of SEQ ID NO:59; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-58 or to the amino acid sequence of SEQ ID NO:112. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-58 or to the amino acid sequence ofSEQ ID NO: 59, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-58. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-58 or to the amino acid sequence of SEQ ID NO:112, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-58. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-58 or to the amino acidsequence of SEQ ID NO: 59 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-58 or theamino acid sequence of SEQ ID NO: 59. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-58 orthe amino acid sequence of SEQ ID NO: 59. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-58 or ofSEQ ID NO: 59, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-58, (b) the HVR-H2 amino acid sequence of antibody AL2p-58, and (c)the HVR-H3 amino acid sequence of antibody AL2p-58. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-58 or to the aminoacid sequence of SEQ ID NO: 112 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-58 or the amino acid sequence of SEQ ID NO: 112. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-58 or the amino acid sequence ofSEQ ID NO: 112. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-58 or of SEQ ID NO: 112, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-58, (b) the HVR-L2 aminoacid sequence of antibody AL2p-58, and (c) the HVR-L3 amino acidsequence of antibody AL2p-58.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-59 or to the amino acid sequence of SEQ ID NO:91; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-59 or to the amino acid sequence of SEQ ID NO:118. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-59 or to the amino acid sequence ofSEQ ID NO: 91, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-59. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-59 or to the amino acid sequence of SEQ ID NO:118, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-59. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-59 or to the amino acidsequence of SEQ ID NO: 91 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-59 or theamino acid sequence of SEQ ID NO: 91. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-59 orthe amino acid sequence of SEQ ID NO: 91. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-59 or ofSEQ ID NO: 91, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-59, (b) the HVR-H2 amino acid sequence of antibody AL2p-59, and (c)the HVR-H3 amino acid sequence of antibody AL2p-59. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-59 or to the aminoacid sequence of SEQ ID NO: 118 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-59 or the amino acid sequence of SEQ ID NO: 118. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-59 or the amino acid sequence ofSEQ ID NO: 118. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-59 or of SEQ ID NO: 118, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-59, (b) the HVR-L2 aminoacid sequence of antibody AL2p-59, and (c) the HVR-L3 amino acidsequence of antibody AL2p-59.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-60 or to the amino acid sequence of SEQ ID NO:53; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-60 or to the amino acid sequence of SEQ ID NO:113. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-60 or to the amino acid sequence ofSEQ ID NO: 53, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-60. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-60 or to the amino acid sequence of SEQ ID NO:113, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-60. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-60 or to the amino acidsequence of SEQ ID NO: 53 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-60 or theamino acid sequence of SEQ ID NO: 53. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-60 orthe amino acid sequence of SEQ ID NO: 53. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-60 or ofSEQ ID NO: 53, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-60, (b) the HVR-H2 amino acid sequence of antibody AL2p-60, and (c)the HVR-H3 amino acid sequence of antibody AL2p-60. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-60 or to the aminoacid sequence of SEQ ID NO: 113 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-60 or the amino acid sequence of SEQ ID NO: 113. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-60 or the amino acid sequence ofSEQ ID NO: 113. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-60 or of SEQ ID NO: 113, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-60, (b) the HVR-L2 aminoacid sequence of antibody AL2p-60, and (c) the HVR-L3 amino acidsequence of antibody AL2p-60.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-61 or to the amino acid sequence of SEQ ID NO:70; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-61 or to the amino acid sequence of SEQ ID NO:110. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-61 or to the amino acid sequence ofSEQ ID NO: 70, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-61. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-61 or to the amino acid sequence of SEQ ID NO:110, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-61. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-61 or to the amino acidsequence of SEQ ID NO: 70 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-61 or theamino acid sequence of SEQ ID NO: 70. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-61 orthe amino acid sequence of SEQ ID NO: 70. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-61 or ofSEQ ID NO: 70, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-61, (b) the HVR-H2 amino acid sequence of antibody AL2p-61, and (c)the HVR-H3 amino acid sequence of antibody AL2p-61. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-61 or to the aminoacid sequence of SEQ ID NO: 110 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-61 or the amino acid sequence of SEQ ID NO: 110. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-61 or the amino acid sequence ofSEQ ID NO: 110. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-61 or of SEQ ID NO: 110, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-61, (b) the HVR-L2 aminoacid sequence of antibody AL2p-61, and (c) the HVR-L3 amino acidsequence of antibody AL2p-61.

In some embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain and a heavy chain variabledomain, wherein the heavy chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a heavy chain variable domain amino acidsequence of antibody AL2p-62 or to the amino acid sequence of SEQ ID NO:71; and/or the light chain variable domain comprises an amino acidsequence with at least 85%, at least 86%, at least 87%, at least 88%, atleast 89%, at least 90%, at least 91%, at least 92%, at least 93%, atleast 94%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-62 or to the amino acid sequence of SEQ ID NO:111. In some embodiments, anti-TREM2 antibodies of the presentdisclosure comprise a heavy chain variable domain comprising an aminoacid sequence with at least 85%, at least 86%, at least 87%, at least88%, at least 89%, at least 90%, at least 91%, at least 92%, at least93%, at least 94%, at least 95%, at least 96%, at least 97%, at least98%, at least 99%, or 100% identity to a heavy chain variable domainamino acid sequence of antibody AL2p-62 or to the amino acid sequence ofSEQ ID NO: 71, wherein the heavy chain variable domain comprises theHVR-H1, HVR-H2, and HVR-H3 amino acid sequences of antibody AL2p-62. Insome embodiments, anti-TREM2 antibodies of the present disclosurecomprise a light chain variable domain comprising an amino acid sequencewith at least 85%, at least 86%, at least 87%, at least 88%, at least89%, at least 90%, at least 91%, at least 92%, at least 93%, at least94%, at least 95%, at least 96%, at least 97%, at least 98%, at least99%, or 100% identity to a light chain variable domain amino acidsequence of antibody AL2p-62 or to the amino acid sequence of SEQ ID NO:111, wherein the light chain variable domain comprises the HVR-L1,HVR-L2, and HVR-L3 amino acid sequences of antibody AL2p-62. In someembodiments, the anti-TREM2 antibody comprises a heavy chain variabledomain (VH) sequence having at least 85%, at least 86%, at least 87%, atleast 88%, at least 89%, at least 90%, at least 91%, at least 92%, atleast 93%, at least 94%, at least 95%, at least 96%, at least 97%, atleast 98%, at least 99%, or 100% identity to a heavy chain variabledomain amino acid sequence of antibody AL2p-62 or to the amino acidsequence of SEQ ID NO: 71 and contains substitutions (e.g., conservativesubstitutions, insertions, or deletions relative to the referencesequence), but the anti-TREM2 antibody comprising that sequence retainsthe ability to bind to TREM2. In certain embodiments, a total of 1 to 10amino acids have been substituted, inserted, and/or deleted in the heavychain variable domain amino acid sequence of antibody AL2p-62 or theamino acid sequence of SEQ ID NO: 71. In certain embodiments, a total of1 to 5 amino acids have been substituted, inserted and/or deleted in theheavy chain variable domain amino acid sequence of antibody AL2p-62 orthe amino acid sequence of SEQ ID NO: 71. In certain embodiments,substitutions, insertions, or deletions occur in regions outside theHVRs (i.e., in the FR regions). In some embodiments, the substitutions,insertions, or deletions occur in in the FR regions. Optionally, theanti-TREM2 antibody comprises the VH sequence of antibody AL2p-62 or ofSEQ ID NO: 71, including post-translational modifications of thatsequence. In a particular embodiment, the VH comprises one, two or threeHVRs selected from: (a) the HVR-H1 amino acid sequence of antibodyAL2p-62, (b) the HVR-H2 amino acid sequence of antibody AL2p-62, and (c)the HVR-H3 amino acid sequence of antibody AL2p-62. In some embodiments,anti-TREM2 antibodies of the present disclosure comprise a light chainvariable domain (VL) sequence having at least 85%, at least 86%, atleast 87%, at least 88%, at least 89%, at least 90%, at least 91%, atleast 92%, at least 93%, at least 94%, at least 95%, at least 96%, atleast 97%, at least 98%, at least 99%, or 100% identity to a light chainvariable domain amino acid sequence of antibody AL2p-62 or to the aminoacid sequence of SEQ ID NO: 111 and contains substitutions (e.g.,conservative substitutions, insertions, or deletions relative to thereference sequence), but the anti-TREM2 antibody comprising thatsequence retains the ability to bind to TREM2. In certain embodiments, atotal of 1 to 10 amino acids have been substituted, inserted, and/ordeleted in the light chain variable domain amino acid sequence ofantibody AL2p-62 or the amino acid sequence of SEQ ID NO: 111. Incertain embodiments, a total of 1 to 5 amino acids have beensubstituted, inserted and/or deleted in the light chain variable domainamino acid sequence of antibody AL2p-62 or the amino acid sequence ofSEQ ID NO: 111. In certain embodiments, substitutions, insertions, ordeletions occur in regions outside the HVRs (i.e., in the FR regions).In some embodiments, the substitutions, insertions, or deletions occurin in the FR regions. Optionally, the anti-TREM2 antibody comprises theVL sequence of antibody AL2p-62 or of SEQ ID NO: 111, includingpost-translational modifications of that sequence. In a particularembodiment, the VL comprises one, two or three HVRs selected from: (a)the HVR-L1 amino acid sequence of antibody AL2p-62, (b) the HVR-L2 aminoacid sequence of antibody AL2p-62, and (c) the HVR-L3 amino acidsequence of antibody AL2p-62.

In some embodiments, the anti-TREM2 antibody is provided, wherein theantibody comprises a VH as in any of the embodiments provided above, anda VL as in any of the embodiments provided above. In some embodiments,provided herein are anti-TREM2 antibodies, wherein the antibodycomprises a VH as in any of the embodiments provided above, and a VL asin any of the embodiments provided above. In one embodiment, theantibody comprises the VH and VL sequences in SEQ ID NOs: 27-71 and 91and SEQ ID NOs: 92-113 and 118, respectively, includingpost-translational modifications of those sequences.

In some embodiments, the antibody comprises a heavy chain variableregion comprising the amino acid sequence of SEQ ID NO: 53, and/or alight chain variable region comprising the amino acid sequence of SEQ IDNO: 97. In some embodiments, the antibody comprises a heavy chainvariable region comprising the amino acid sequence of SEQ ID NO: 59;and/or a light chain variable region comprising the amino acid sequenceof SEQ ID NO: 104. In some embodiments, the antibody comprises a heavychain variable region comprising the amino acid sequence of SEQ ID NO:64; and/or a light chain variable region comprising the amino acidsequence of SEQ ID NO: 108. In some embodiments, the antibody comprisesa heavy chain variable region comprising the amino acid sequence of SEQID NO: 70; and/or a light chain variable region comprising the aminoacid sequence of SEQ ID NO: 110. In some embodiments, the antibodycomprises a heavy chain variable region comprising the amino acidsequence of SEQ ID NO: 71; and/or a light chain variable regioncomprising the amino acid sequence of SEQ ID NO: 111. In someembodiments, the antibody comprises a heavy chain variable regioncomprising the amino acid sequence of SEQ ID NO: 59; and/or a lightchain variable region comprising the amino acid sequence of SEQ ID NO:112. In some embodiments, the antibody comprises a heavy chain variableregion comprising the amino acid sequence of SEQ ID NO: 53; and/or alight chain variable region comprising the amino acid sequence of SEQ IDNO: 113.

Any of the antibodies of the present disclosure may be produced by acell line. In some embodiments, the cell line may be a mammalian cellline. In certain embodiments, the cell line may be a hybridoma cellline. In other embodiments, the cell line may be a yeast cell line. Anycell line known in the art suitable for antibody production may be usedto produce an antibody of the present disclosure. Exemplary cell linesfor antibody production are described throughout the present disclosure.

In some embodiments, the anti-TREM2 antibody is an anti-TREM2 monoclonalantibody selected from AL2p-h50, AL2p-2, AL2p-3, AL2p-4, AL2p-5, AL2p-6,AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14,AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22,AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30,AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36, AL2p-37, AL2p-38,AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46,AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54,AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60, AL2p-61, AL2p-62,AL2p-h19, AL2p-h21, AL2p-h22, AL2p-h23, AL2p-h24, AL2p-h25, AL2p-h26,AL2p-h27, AL2p-h28, AL2p-h29, AL2p-h30, AL2p-h31, AL2p-h32, AL2p-h33,AL2p-h34, AL2p-h35, AL2p-h36, AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47,AL2p-h59, AL2p-h76, and AL2p-h90.

In some embodiments, the anti-TREM2 antibody is anti-TREM2 monoclonalantibody AL2p-31. In some embodiments, the anti-TREM2 antibody is anisolated antibody which binds essentially the same TREM2 epitope asAL2p-31. In some embodiments, the anti-TREM2 antibody is an isolatedantibody comprising the HVR-H1, HVR-H2, and HVR-H3 of the heavy chainvariable domain of monoclonal antibody AL2p-31. In some embodiments, theanti-TREM2 antibody is an isolated antibody comprising the HVR-L1,HVR-L2, and HVR-L3 of the light chain variable domain of monoclonalantibody AL2p-31. In some embodiments, the anti-TREM2 antibody is anisolated antibody comprising the HVR-H1, HVR-H2, and HVR-H3 of the heavychain variable domain and the HVR-L1, HVR-L2, and HVR-L3 of the lightchain variable domain of monoclonal antibody AL2p-31.

In some embodiments, the anti-TREM2 antibody is anti-TREM2 monoclonalantibody AL2p-37. In some embodiments, the anti-TREM2 antibody is anisolated antibody which binds essentially the same TREM2 epitope asAL2p-37. In some embodiments, the anti-TREM2 antibody is an isolatedantibody comprising the HVR-H1, HVR-H2, and HVR-H3 of the heavy chainvariable domain of monoclonal antibody AL2p-37. In some embodiments, theanti-TREM2 antibody is an isolated antibody comprising the HVR-L1,HVR-L2, and HVR-L3 of the light chain variable domain of monoclonalantibody AL2p-37. In some embodiments, the anti-TREM2 antibody is anisolated antibody comprising the HVR-H1, HVR-H2, and HVR-H3 of the heavychain variable domain and the HVR-L1, HVR-L2, and HVR-L3 of the lightchain variable domain of monoclonal antibody AL2p-37.

In some embodiments, the anti-TREM2 antibody is anti-TREM2 monoclonalantibody AL2p-47. In some embodiments, the anti-TREM2 antibody is anisolated antibody which binds essentially the same TREM2 epitope asAL2p-47. In some embodiments, the anti-TREM2 antibody is an isolatedantibody comprising the HVR-H1, HVR-H2, and HVR-H3 of the heavy chainvariable domain of monoclonal antibody AL2p-47. In some embodiments, theanti-TREM2 antibody is an isolated antibody comprising the HVR-L1,HVR-L2, and HVR-L3 of the light chain variable domain of monoclonalantibody AL2p-47. In some embodiments, the anti-TREM2 antibody is anisolated antibody comprising the HVR-H1, HVR-H2, and HVR-H3 of the heavychain variable domain and the HVR-L1, HVR-L2, and HVR-L3 of the lightchain variable domain of monoclonal antibody AL2p-47.

In some embodiments, the anti-TREM2 antibody is anti-TREM2 monoclonalantibody AL2p-58. In some embodiments, the anti-TREM2 antibody is anisolated antibody which binds essentially the same TREM2 epitope asAL2p-58. In some embodiments, the anti-TREM2 antibody is an isolatedantibody comprising the HVR-H1, HVR-H2, and HVR-H3 of the heavy chainvariable domain of monoclonal antibody AL2p-58. In some embodiments, theanti-TREM2 antibody is an isolated antibody comprising the HVR-L1,HVR-L2, and HVR-L3 of the light chain variable domain of monoclonalantibody AL2p-58. In some embodiments, the anti-TREM2 antibody is anisolated antibody comprising the HVR-H1, HVR-H2, and HVR-H3 of the heavychain variable domain and the HVR-L1, HVR-L2, and HVR-L3 of the lightchain variable domain of monoclonal antibody AL2p-58.

In some embodiments, the anti-TREM2 antibody is anti-TREM2 monoclonalantibody AL2p-60. In some embodiments, the anti-TREM2 antibody is anisolated antibody which binds essentially the same TREM2 epitope asAL2p-60. In some embodiments, the anti-TREM2 antibody is an isolatedantibody comprising the HVR-H1, HVR-H2, and HVR-H3 of the heavy chainvariable domain of monoclonal antibody AL2p-60. In some embodiments, theanti-TREM2 antibody is an isolated antibody comprising the HVR-L1,HVR-L2, and HVR-L3 of the light chain variable domain of monoclonalantibody AL2p-60. In some embodiments, the anti-TREM2 antibody is anisolated antibody comprising the HVR-H1, HVR-H2, and HVR-H3 of the heavychain variable domain and the HVR-L1, HVR-L2, and HVR-L3 of the lightchain variable domain of monoclonal antibody AL2p-60.

In some embodiments, the anti-TREM2 antibody is anti-TREM2 monoclonalantibody AL2p-61. In some embodiments, the anti-TREM2 antibody is anisolated antibody which binds essentially the same TREM2 epitope asAL2p-61. In some embodiments, the anti-TREM2 antibody is an isolatedantibody comprising the HVR-H1, HVR-H2, and HVR-H3 of the heavy chainvariable domain of monoclonal antibody AL2p-61. In some embodiments, theanti-TREM2 antibody is an isolated antibody comprising the HVR-L1,HVR-L2, and HVR-L3 of the light chain variable domain of monoclonalantibody AL2p-61. In some embodiments, the anti-TREM2 antibody is anisolated antibody comprising the HVR-H1, HVR-H2, and HVR-H3 of the heavychain variable domain and the HVR-L1, HVR-L2, and HVR-L3 of the lightchain variable domain of monoclonal antibody AL2p-61.

In some embodiments, the anti-TREM2 antibody is anti-TREM2 monoclonalantibody AL2p-62. In some embodiments, the anti-TREM2 antibody is anisolated antibody which binds essentially the same TREM2 epitope asAL2p-62. In some embodiments, the anti-TREM2 antibody is an isolatedantibody comprising the HVR-H1, HVR-H2, and HVR-H3 of the heavy chainvariable domain of monoclonal antibody AL2p-62. In some embodiments, theanti-TREM2 antibody is an isolated antibody comprising the HVR-L1,HVR-L2, and HVR-L3 of the light chain variable domain of monoclonalantibody AL2p-62. In some embodiments, the anti-TREM2 antibody is anisolated antibody comprising the HVR-H1, HVR-H2, and HVR-H3 of the heavychain variable domain and the HVR-L1, HVR-L2, and HVR-L3 of the lightchain variable domain of monoclonal antibody AL2p-62.

In some embodiments, anti-TREM2 antibodies of the present disclosure donot compete with one or more TREM2 ligands for binding to TREM2. In someembodiments, anti-TREM2 antibodies of the present disclosure are capableof binding TREM2 without blocking simultaneous binding of one or moreTREM2 ligands to TREM2. In some embodiments anti-TREM2 antibodies of thepresent disclosure are capable of additive and/or synergistic functionalinteractions with one or more TREM2 ligands. In some embodiments,anti-TREM2 antibodies of the present disclosure increase the maximalactivity of TREM2 exposed to saturating concentrations of one or moreTREM2 ligands. In some embodiments, anti-TREM2 antibodies of the presentdisclosure increase the activity of TREM2 obtained at any concentrationof one or more TREM2 ligands.

Anti-TREM2 Antibody Binding Affinity

The dissociation constants (K_(D)) of anti-TREM2 antibodies for humanTREM2 and cynomolgus monkey TREM2 may be at least 1-fold lower, at least2-fold lower, at least 3-fold lower, at least 4-fold lower, at least5-fold lower, at least 6-fold lower, at least 7-fold lower, at least8-fold lower, at least 9-fold lower, at least 10-fold lower, at least11-fold lower, at least 12-fold lower, at least 13-fold lower, at least14-fold lower, at least 15-fold lower, at least 16-fold lower, at least17-fold lower, at least 18-fold lower, at least 19-fold lower, at least20-fold lower or lower than an anti-TREM2 antibody selected from ananti-TREM2 antibody comprising a heavy chain variable region comprisingthe amino acid sequence of SEQ ID NO: 27 and comprising light chainvariable region comprising the amino acid sequence of SEQ ID NO: 56; ananti-TREM2 antibody comprising a heavy chain variable region comprisingthe amino acid sequence of SEQ ID NO: 91 and a light chain variableregion comprising the amino acid sequence of SEQ ID NO: 103; and ananti-TREM2 antibody comprising a heavy chain variable region comprisingthe amino acid sequence of SEQ ID NO: 119 and a light chain variableregion comprising the amino acid sequence of SEQ ID NO: 120. In someembodiments, the dissociation constant (K_(D)) is determined at atemperature of approximately 25° C. In some embodiments, the K_(D) isdetermined using a monovalent antibody (e.g., a Fab) or a full-lengthantibody in a monovalent form. Methods for the preparation and selectionof antibodies that interact and/or bind with specificity to TREM2 aredescribed herein. (e.g., see Examples 1 and 2).

In some embodiments, the dissociation constants (K_(D)) of anti-TREM2antibodies for human TREM2 may range from about 300 nM to about 100 pM,from about 200 nM to about 100 pM, from about 100 nM to about 100 pM,from about 90 nM to about 100 pM, from about 80 nM to about 100 pM, fromabout 70 nM to about 100 pM, from about 60 nM to about 100 pM, fromabout 50 nM to about 100 pM, from about 40 nM to about 100 pM, fromabout 30 nM to about 100 pM, from about 20 nM to about 100 pM, fromabout 10 nM to about 100 pM, from about 9 nM to about 100 pM, from about8 nM to about 100 pM, from about 7 nM to about 100 pM, from about 6 nMto about 100 pM, from about 5 nM to about 100 pM, from about 4 nM toabout 100 pM, from about 3 nM to about 100 pM, from about 2 nM to about100 pM, from about 1 nM to about 100 pM, from 900 pM to about 100 pM,from about 800 pM to about 100 pM, from 700 pM to about 100 pM, from 600pM to about 500 pM, from 400 pM to about 100 pM, from 300 pM to about100 pM, from 200 pM to about 100 pM, from 900 pM to about 100 pM, orless than 100 pM. In some embodiments, the dissociation constant (K_(D))is determined at a temperature of approximately 25° C. In someembodiments, the K_(D) is determined using a monovalent antibody (e.g.,a Fab) or a full-length antibody in a monovalent form. Methods for thepreparation and selection of antibodies that interact and/or bind withspecificity to TREM2 are described herein. (e.g., see Examples 1 and 2).

In some embodiments, the dissociation constants (K_(D)) of anti-TREM2antibodies for human TREM2 may range from about 300 nM to about 90 pM,from about 300 nM to about 80 pM, from about 300 nM to about 70 pM, fromabout 300 nM to about 60 pM, from about 300 nM to about 50 pM, fromabout 300 nM to about 40 pM, from about 300 nM to about 30 pM, fromabout 300 nM to about 20 pM, from about 300 nM to about 10 pM, fromabout 300 nM to about 9 pM, from about 300 nM to about 8 pM, from about300 nM to about 7 pM, from about 300 nM to about 6 pM, from about 300 nMto about 5 pM, from about 300 nM to about 4 pM, from about 300 nM toabout 3 pM, from about 300 nM to about 2 pM, from about 300 nM to about1 pM, or less than 1 pM. The dissociation constants (K_(D)) ofanti-TREM2 antibodies for human TREM2 may range from about 200 nM toabout 90 pM, from about 200 nM to about 80 pM, from about 200 nM toabout 70 pM, from about 200 nM to about 60 pM, from about 200 nM toabout 50 pM, from about 200 nM to about 40 pM, from about 200 nM toabout 30 pM, from about 200 nM to about 20 pM, from about 200 nM toabout 10 pM, from about 200 nM to about 9 pM, from about 200 nM to about8 pM, from about 200 nM to about 7 pM, from about 200 nM to about 6 pM,from about 200 nM to about 5 pM, from about 200 nM to about 4 pM, fromabout 200 nM to about 3 pM, from about 200 nM to about 2 pM, from about200 nM to about 1 pM, or less than 1 pM. The dissociation constants(K_(D)) of anti-TREM2 antibodies for human TREM2 may range from about100 nM to about 90 pM, from about 100 nM to about 80 pM, from about 100nM to about 70 pM, from about 100 nM to about 60 pM, from about 100 nMto about 50 pM, from about 100 nM to about 40 pM, from about 100 nM toabout 30 pM, from about 100 nM to about 20 pM, from about 100 nM toabout 10 pM, from about 100 nM to about 9 pM, from about 100 nM to about8 pM, from about 100 nM to about 7 pM, from about 100 nM to about 6 pM,from about 100 nM to about 5 pM, from about 100 nM to about 4 pM, fromabout 100 nM to about 3 pM, from about 100 nM to about 2 pM, from about100 nM to about 1 pM, or less than 1 pM. The dissociation constants(K_(D)) of anti-TREM2 antibodies for human TREM2 may range from about 90nM to about 90 pM, from about 90 nM to about 80 pM, from about 90 nM toabout 70 pM, from about 90 nM to about 60 pM, from about 90 nM to about50 pM, from about 90 nM to about 40 pM, from about 90 nM to about 30 pM,from about 90 nM to about 20 pM, from about 90 nM to about 10 pM, fromabout 90 nM to about 9 pM, from about 90 nM to about 8 pM, from about 90nM to about 7 pM, from about 90 nM to about 6 pM, from about 90 nM toabout 5 pM, from about 90 nM to about 4 pM, from about 90 nM to about 3pM, from about 90 nM to about 2 pM, from about 90 nM to about 1 pM, orless than 1 pM. The dissociation constants (K_(D)) of anti-TREM2antibodies for human TREM2 may range from about 80 nM to about 90 pM,from about 80 nM to about 80 pM, from about 80 nM to about 70 pM, fromabout 80 nM to about 60 pM, from about 80 nM to about 50 pM, from about80 nM to about 40 pM, from about 80 nM to about 30 pM, from about 80 nMto about 20 pM, from about 80 nM to about 10 pM, from about 80 nM toabout 9 pM, from about 80 nM to about 8 pM, from about 80 nM to about 7pM, from about 80 nM to about 6 pM, from about 80 nM to about 5 pM, fromabout 80 nM to about 4 pM, from about 80 nM to about 3 pM, from about 80nM to about 2 pM, from about 80 nM to about 1 pM, or less than 1 pM. Thedissociation constants (K_(D)) of anti-TREM2 antibodies for human TREM2may range from about 70 nM to about 90 pM, from about 70 nM to about 80pM, from about 70 nM to about 70 pM, from about 70 nM to about 60 pM,from about 70 nM to about 50 pM, from about 70 nM to about 40 pM, fromabout 70 nM to about 30 pM, from about 70 nM to about 20 pM, from about70 nM to about 10 pM, from about 70 nM to about 9 pM, from about 70 nMto about 8 pM, from about 70 nM to about 7 pM, from about 70 nM to about6 pM, from about 70 nM to about 5 pM, from about 70 nM to about 4 pM,from about 70 nM to about 3 pM, from about 70 nM to about 2 pM, fromabout 70 nM to about 1 pM, or less than 1 pM. The dissociation constants(K_(D)) of anti-TREM2 antibodies for human TREM2 may range from about 60nM to about 90 pM, from about 60 nM to about 80 pM, from about 60 nM toabout 70 pM, from about 60 nM to about 60 pM, from about 60 nM to about50 pM, from about 60 nM to about 40 pM, from about 60 nM to about 30 pM,from about 60 nM to about 20 pM, from about 60 nM to about 10 pM, fromabout 60 nM to about 9 pM, from about 60 nM to about 8 pM, from about 60nM to about 7 pM, from about 60 nM to about 6 pM, from about 60 nM toabout 5 pM, from about 60 nM to about 4 pM, from about 60 nM to about 3pM, from about 60 nM to about 2 pM, from about 60 nM to about 1 pM, orless than 1 pM. The dissociation constants (K_(D)) of anti-TREM2antibodies for human TREM2 may range from about 50 nM to about 90 pM,from about 50 nM to about 80 pM, from about 50 nM to about 70 pM, fromabout 50 nM to about 60 pM, from about 50 nM to about 50 pM, from about50 nM to about 40 pM, from about 50 nM to about 30 pM, from about 50 nMto about 20 pM, from about 50 nM to about 10 pM, from about 50 nM toabout 9 pM, from about 50 nM to about 8 pM, from about 50 nM to about 7pM, from about 50 nM to about 6 pM, from about 50 nM to about 5 pM, fromabout 50 nM to about 4 pM, from about 50 nM to about 3 pM, from about 50nM to about 2 pM, from about 50 nM to about 1 pM, or less than 1 pM. Thedissociation constants (K_(D)) of anti-TREM2 antibodies for human TREM2may range from about 40 nM to about 90 pM, from about 40 nM to about 80pM, from about 40 nM to about 70 pM, from about 40 nM to about 60 pM,from about 40 nM to about 50 pM, from about 40 nM to about 40 pM, fromabout 40 nM to about 30 pM, from about 40 nM to about 20 pM, from about40 nM to about 10 pM, from about 40 nM to about 9 pM, from about 40 nMto about 8 pM, from about 40 nM to about 7 pM, from about 40 nM to about6 pM, from about 40 nM to about 5 pM, from about 40 nM to about 4 pM,from about 40 nM to about 3 pM, from about 40 nM to about 2 pM, fromabout 40 nM to about 1 pM, or less than 1 pM. The dissociation constants(K_(D)) of anti-TREM2 antibodies for human TREM2 may range from about 30nM to about 90 pM, from about 30 nM to about 80 pM, from about 30 nM toabout 70 pM, from about 30 nM to about 60 pM, from about 30 nM to about50 pM, from about 30 nM to about 40 pM, from about 30 nM to about 30 pM,from about 30 nM to about 20 pM, from about 30 nM to about 10 pM, fromabout 30 nM to about 9 pM, from about 30 nM to about 8 pM, from about 30nM to about 7 pM, from about 30 nM to about 6 pM, from about 30 nM toabout 5 pM, from about 30 nM to about 4 pM, from about 30 nM to about 3pM, from about 30 nM to about 2 pM, from about 30 nM to about 1 pM, orless than 1 pM. The dissociation constants (K_(D)) of anti-TREM2antibodies for human TREM2 may range from about 20 nM to about 90 pM,from about 20 nM to about 80 pM, from about 20 nM to about 70 pM, fromabout 20 nM to about 60 pM, from about 20 nM to about 50 pM, from about20 nM to about 40 pM, from about 20 nM to about 30 pM, from about 20 nMto about 20 pM, from about 20 nM to about 10 pM, from about 20 nM toabout 9 pM, from about 20 nM to about 8 pM, from about 20 nM to about 7pM, from about 20 nM to about 6 pM, from about 20 nM to about 5 pM, fromabout 20 nM to about 4 pM, from about 20 nM to about 3 pM, from about 20nM to about 2 pM, from about 20 nM to about 1 pM, or less than 1 pM. Thedissociation constants (K_(D)) of anti-TREM2 antibodies for human TREM2may range from about 10 nM to about 90 pM, from about 10 nM to about 80pM, from about 10 nM to about 70 pM, from about 10 nM to about 60 pM,from about 10 nM to about 50 pM, from about 10 nM to about 40 pM, fromabout 10 nM to about 30 pM, from about 10 nM to about 20 pM, from about10 nM to about 10 pM, from about 10 nM to about 9 pM, from about 10 nMto about 8 pM, from about 10 nM to about 7 pM, from about 10 nM to about6 pM, from about 10 nM to about 5 pM, from about 10 nM to about 4 pM,from about 10 nM to about 3 pM, from about 10 nM to about 2 pM, fromabout 10 nM to about 1 pM, or less than 1 pM. The dissociation constants(K_(D)) of anti-TREM2 antibodies for human TREM2 may range from about 5nM to about 90 pM, from about 5 nM to about 80 pM, from about 5 nM toabout 70 pM, from about 5 nM to about 60 pM, from about 5 nM to about 50pM, from about 5 nM to about 40 pM, from about 5 nM to about 30 pM, fromabout 5 nM to about 20 pM, from about 5 nM to about 10 pM, from about 5nM to about 9 pM, from about 5 nM to about 8 pM, from about 5 nM toabout 7 pM, from about 5 nM to about 6 pM, from about 5 nM to about 5pM, from about 5 nM to about 4 pM, from about 5 nM to about 3 pM, fromabout 5 nM to about 2 pM, from about 5 nM to about 1 pM, or less than 1pM. The dissociation constants (K_(D)) of anti-TREM2 antibodies forhuman TREM2 may range from about 1 nM to about 90 pM, from about 1 nM toabout 80 pM, from about 1 nM to about 70 pM, from about 1 nM to about 60pM, from about 1 nM to about 50 pM, from about 1 nM to about 40 pM, fromabout 1 nM to about 30 pM, from about 1 nM to about 20 pM, from about 1nM to about 10 pM, from about 1 nM to about 9 pM, from about 1 nM toabout 8 pM, from about 1 nM to about 7 pM, from about 1 nM to about 6pM, from about 1 nM to about 5 pM, from about 1 nM to about 4 pM, fromabout 1 nM to about 3 pM, from about 1 nM to about 2 pM, from about 1 nMto about 1 pM, or less than 1 pM. The dissociation constants (K_(D)) ofanti-TREM2 antibodies for human TREM2 may range from about 500 pM toabout 90 pM, from about 500 pM to about 80 pM, from about 500 pM toabout 70 pM, from about 500 pM to about 60 pM, from about 500 pM toabout 50 pM, from about 500 pM to about 40 pM, from about 500 pM toabout 30 pM, from about 500 pM to about 20 pM, from about 500 pM toabout 10 pM, from about 500 pM to about 9 pM, from about 500 pM to about8 pM, from about 500 pM to about 7 pM, from about 500 pM to about 6 pM,from about 500 pM to about 5 pM, from about 500 pM to about 4 pM, fromabout 500 pM to about 3 pM, from about 500 pM to about 2 pM, from about500 pM to about 1 pM, or less than 1 pM. The dissociation constants(K_(D)) of anti-TREM2 antibodies for human TREM2 may range from about250 pM to about 90 pM, from about 250 pM to about 80 pM, from about 250pM to about 70 pM, from about 250 pM to about 60 pM, from about 250 pMto about 50 pM, from about 250 pM to about 40 pM, from about 250 pM toabout 30 pM, from about 250 pM to about 20 pM, from about 250 pM toabout 10 pM, from about 250 pM to about 9 pM, from about 250 pM to about8 pM, from about 250 pM to about 7 pM, from about 250 pM to about 6 pM,from about 250 pM to about 5 pM, from about 250 pM to about 4 pM, fromabout 250 pM to about 3 pM, from about 250 pM to about 2 pM, from about250 pM to about 1 pM, or less than 1 pM. The dissociation constants(K_(D)) of anti-TREM2 antibodies for human TREM2 may range from about100 pM to about 90 pM, from about 100 pM to about 80 pM, from about 100pM to about 70 pM, from about 100 pM to about 60 pM, from about 100 pMto about 50 pM, from about 100 pM to about 40 pM, from about 100 pM toabout 30 pM, from about 100 pM to about 20 pM, from about 100 pM toabout 10 pM, from about 100 pM to about 9 pM, from about 100 pM to about8 pM, from about 100 pM to about 7 pM, from about 100 pM to about 6 pM,from about 100 pM to about 5 pM, from about 100 pM to about 4 pM, fromabout 100 pM to about 3 pM, from about 100 pM to about 2 pM, from about100 pM to about 1 pM, or less than 1 pM. In some embodiments, thedissociation constant (K_(D)) is determined at a temperature ofapproximately 25° C. In some embodiments, the K_(D) is determined usinga monovalent antibody (e.g., a Fab) or a full-length antibody in amonovalent form. Methods for the preparation and selection of antibodiesthat interact and/or bind with specificity to TREM2 are describedherein. (e.g., see Examples 1 and 2).

In some embodiments, the dissociation constants (K_(D)) of anti-TREM2antibodies for human TREM2 may be less than 260 nM, may be less than 225nM, may be less than 200 nM, may be less than 150 nM, may be less than135 nM, may be less than 125 nM, may be less than 100 nM, may be lessthan 95 nM, may be less than 90 nM, may be less than 85 nM, may be lessthan 80 nM, may be less than 75 nM, may be less than 70 nM, may be lessthan 65 nM, may be less than 60 nM, may be less than 55 nM, may be lessthan 50 nM, may be less than 45 nM, may be less than 40 nM, may be lessthan 36 nM, may be less than 35 nM, may be less than 30 nM, may be lessthan 29 nM, may be less than 28 nM, may be less than 27 nM, may be lessthan 26 nM, may be less than 25 nM, may be less than 24 nM, may be lessthan 23 nM, may be less than 22 nM, may be less than 21 nM, may be lessthan 20 nM, may be less than 19 nM, may be less than 18.5 nM, may beless than 18 nM, may be less than 15 nM, may be less than 14 nM, may beless than 13 nM, may be less than 12 nM, may be less than 11 nM, may beless than 10 nM, may be less than 9.5 nM, may be less than 9 nM, may beless than 8.5 nM, may be less than 8 nM, may be less than 7.5 nM, may beless than 7 nM, may be less than 6.5 nM, may be less than 6 nM, may beless than 5.5 nM, may be less than 5 nM, may be less than 4.5 nM, may beless than 4 nM, may be less than 3.5 nM, may be less than 3 nM, may beless than 2.5 nM, may be less than 2 nM, may be less than 1.5 nM, may beless than 1 nM, may be less than 950 pM, may be less than 900 pM, may beless than 850 pM, may be less than 830 pM, may be less than 800 pM, maybe less than 750 pM, may be less than 730 pM, may be less than 700 pM,may be less than 650 pM, may be less than 630 pM, may be less than 600pM, may be less than 550 pM, may be less than 500 pM, may be less than450 pM, may be less than 415 pM, may be less than 400 pM, may be lessthan 350 pM, may be less than 300 pM, may be less than 250 pM, may beless than 200 pM, may be less than 150 pM, may be less than 100 pM, maybe less than 95 pM, may be less than 90 pM, may be less than 85 pM, maybe less than 80 pM, may be less than 75 pM, may be less than 70 pM, maybe less than 65 pM, may be less than 60 pM, may be less than 55 pM, maybe less than 50 pM, may be less than 45 pM, may be less than 40 pM, maybe less than 35 pM, may be less than 30 pM, may be less than 25 pM, maybe less than 20 pM, may be less than 15 pM, may be less than 10 pM, maybe less than 9 pM, may be less than 8 pM, may be less than 7 pM, may beless than 6 pM, may be less than 5 pM, may be less than 4 pM, may beless than 3 pM, may be less than 2 pM, or may be less than 1 pM. In someembodiments, the dissociation constant (K_(D)) is determined at atemperature of approximately 25° C. In some embodiments, the K_(D) isdetermined using a monovalent antibody (e.g., a Fab) or a full-lengthantibody in a monovalent form. Methods for the preparation and selectionof antibodies that interact and/or bind with specificity to TREM2 aredescribed herein. (e.g., see Examples 1 and 2).

In some embodiments, the dissociation constants (K_(D)) of anti-TREM2antibodies for cynomolgus monkey TREM2 may range from about 10 μM toabout 100 pM, from about 200 nM to about 100 pM, from about 100 nM toabout 100 pM, from about 90 nM to about 100 pM, from about 80 nM toabout 100 pM, from about 70 nM to about 100 pM, from about 60 nM toabout 100 pM, from about 50 nM to about 100 pM, from about 40 nM toabout 100 pM, from about 30 nM to about 100 pM, from about 20 nM toabout 100 pM, from about 10 nM to about 100 pM, from about 9 nM to about100 pM, from about 8 nM to about 100 pM, from about 7 nM to about 100pM, from about 6 nM to about 100 pM, from about 5 nM to about 100 pM,from about 4 nM to about 100 pM, from about 3 nM to about 100 pM, fromabout 2 nM to about 100 pM, from about 1 nM to about 100 pM, from 900 pMto about 100 pM, from about 800 pM to about 100 pM, from 700 pM to about100 pM, from 600 pM to about 500 pM, from 400 pM to about 100 pM, from300 pM to about 100 pM, from 200 pM to about 100 pM, from 900 pM toabout 100 pM, or less than 100 pM. In some embodiments, the dissociationconstant (K_(D)) is determined at a temperature of approximately 25° C.In some embodiments, the K_(D) is determined using a monovalent antibody(e.g., a Fab) or a full-length antibody in a monovalent form. Methodsfor the preparation and selection of antibodies that interact and/orbind with specificity to TREM2 are described herein. (e.g., see Examples1 and 2).

In some embodiments, the dissociation constants (K_(D)) of anti-TREM2antibodies for cynomolgus monkey TREM2 may range from about 10 μM toabout 900 pM, from about 10 μM to about 800 pM, from about 10 μM toabout 700 pM, from about 10 μM to about 600 pM, from about 10 μM toabout 500 pM, from about 10 μM to about 400 pM, from about 10 μM toabout 300 pM, from about 10 μM to about 200 pM, from about 10 μM toabout 100 pM, or less than 100 pM. In some embodiments, the dissociationconstants (K_(D)) of anti-TREM2 antibodies for cynomolgus monkey TREM2may range from about 5 μM to about 900 pM, from about 5 μM to about 800pM, from about 5 μM to about 700 pM, from about 5 μM to about 600 pM,from about 5 μM to about 500 pM, from about 5 μM to about 400 pM, fromabout 5 μM to about 300 pM, from about 5 μM to about 200 pM, from about5 μM to about 100 pM, or less than 100 pM. In some embodiments, thedissociation constants (K_(D)) of anti-TREM2 antibodies for cynomolgusmonkey TREM2 may range from about 1 μM to about 900 pM, from about 1 μMto about 800 pM, from about 1 μM to about 700 pM, from about 1 μM toabout 600 pM, from about 1 μM to about 500 pM, from about 1 μM to about400 pM, from about 1 μM to about 300 pM, from about 1 μM to about 200pM, from about 1 μM to about 100 pM, or less than 100 pM. In someembodiments, the dissociation constants (K_(D)) of anti-TREM2 antibodiesfor cynomolgus monkey TREM2 may range from about 900 nM to about 900 pM,from about 900 nM to about 800 pM, from about 900 nM to about 700 pM,from about 900 nM to about 600 pM, from about 900 nM to about 500 pM,from about 900 nM to about 400 pM, from about 900 nM to about 300 pM,from about 900 nM to about 200 pM, from about 900 nM to about 100 pM, orless than 100 pM. In some embodiments, the dissociation constants(K_(D)) of anti-TREM2 antibodies for cynomolgus monkey TREM2 may rangefrom about 800 nM to about 900 pM, from about 800 nM to about 800 pM,from about 800 nM to about 700 pM, from about 800 nM to about 600 pM,from about 800 nM to about 500 pM, from about 800 nM to about 400 pM,from about 800 nM to about 300 pM, from about 800 nM to about 200 pM,from about 800 nM to about 100 pM, or less than 100 pM. In someembodiments, the dissociation constants (K_(D)) of anti-TREM2 antibodiesfor cynomolgus monkey TREM2 may range from about 700 nM to about 900 pM,from about 700 nM to about 800 pM, from about 700 nM to about 700 pM,from about 700 nM to about 600 pM, from about 700 nM to about 500 pM,from about 700 nM to about 400 pM, from about 700 nM to about 300 pM,from about 700 nM to about 200 pM, from about 700 nM to about 100 pM, orless than 100 pM. In some embodiments, the dissociation constants(K_(D)) of anti-TREM2 antibodies for cynomolgus monkey TREM2 may rangefrom about 600 nM to about 900 pM, from about 600 nM to about 800 pM,from about 600 nM to about 700 pM, from about 600 nM to about 600 pM,from about 600 nM to about 500 pM, from about 600 nM to about 400 pM,from about 600 nM to about 300 pM, from about 600 nM to about 200 pM,from about 600 nM to about 100 pM, or less than 100 pM. In someembodiments, the dissociation constants (K_(D)) of anti-TREM2 antibodiesfor cynomolgus monkey TREM2 may range from about 500 nM to about 900 pM,from about 500 nM to about 800 pM, from about 500 nM to about 700 pM,from about 500 nM to about 600 pM, from about 500 nM to about 500 pM,from about 500 nM to about 400 pM, from about 500 nM to about 300 pM,from about 500 nM to about 200 pM, from about 500 nM to about 100 pM, orless than 100 pM. In some embodiments, the dissociation constants(K_(D)) of anti-TREM2 antibodies for cynomolgus monkey TREM2 may rangefrom about 400 nM to about 900 pM, from about 400 nM to about 800 pM,from about 400 nM to about 700 pM, from about 400 nM to about 600 pM,from about 400 nM to about 500 pM, from about 400 nM to about 400 pM,from about 400 nM to about 300 pM, from about 400 nM to about 200 pM,from about 400 nM to about 100 pM, or less than 100 pM. In someembodiments, the dissociation constants (K_(D)) of anti-TREM2 antibodiesfor cynomolgus monkey TREM2 may range from about 300 nM to about 900 pM,from about 300 nM to about 800 pM, from about 300 nM to about 700 pM,from about 300 nM to about 600 pM, from about 300 nM to about 500 pM,from about 300 nM to about 400 pM, from about 300 nM to about 300 pM,from about 300 nM to about 200 pM, from about 300 nM to about 100 pM, orless than 100 pM. In some embodiments, the dissociation constants(K_(D)) of anti-TREM2 antibodies for cynomolgus monkey TREM2 may rangefrom about 200 nM to about 900 pM, from about 200 nM to about 800 pM,from about 200 nM to about 700 pM, from about 200 nM to about 600 pM,from about 200 nM to about 500 pM, from about 200 nM to about 400 pM,from about 200 nM to about 300 pM, from about 200 nM to about 200 pM,from about 200 nM to about 100 pM, or less than 100 pM. In someembodiments, the dissociation constants (K_(D)) of anti-TREM2 antibodiesfor cynomolgus monkey TREM2 may range from about 100 nM to about 900 pM,from about 100 nM to about 800 pM, from about 100 nM to about 700 pM,from about 100 nM to about 600 pM, from about 100 nM to about 500 pM,from about 100 nM to about 400 pM, from about 100 nM to about 300 pM,from about 100 nM to about 200 pM, from about 100 nM to about 100 pM, orless than 100 pM. In some embodiments, the dissociation constants(K_(D)) of anti-TREM2 antibodies for cynomolgus monkey TREM2 may rangefrom about 90 nM to about 900 pM, from about 90 nM to about 800 pM, fromabout 90 nM to about 700 pM, from about 90 nM to about 600 pM, fromabout 90 nM to about 500 pM, from about 90 nM to about 400 pM, fromabout 90 nM to about 300 pM, from about 90 nM to about 200 pM, fromabout 90 nM to about 100 pM, or less than 100 pM. In some embodiments,the dissociation constants (K_(D)) of anti-TREM2 antibodies forcynomolgus monkey TREM2 may range from about 80 nM to about 900 pM, fromabout 80 nM to about 800 pM, from about 80 nM to about 700 pM, fromabout 80 nM to about 600 pM, from about 80 nM to about 500 pM, fromabout 80 nM to about 400 pM, from about 80 nM to about 300 pM, fromabout 80 nM to about 200 pM, from about 80 nM to about 100 pM, or lessthan 100 pM. In some embodiments, the dissociation constants (K_(D)) ofanti-TREM2 antibodies for cynomolgus monkey TREM2 may range from about70 nM to about 900 pM, from about 70 nM to about 800 pM, from about 70nM to about 700 pM, from about 70 nM to about 600 pM, from about 70 nMto about 500 pM, from about 70 nM to about 400 pM, from about 70 nM toabout 300 pM, from about 70 nM to about 200 pM, from about 70 nM toabout 100 pM, or less than 100 pM. In some embodiments, the dissociationconstants (K_(D)) of anti-TREM2 antibodies for cynomolgus monkey TREM2may range from about 60 nM to about 900 pM, from about 60 nM to about800 pM, from about 60 nM to about 700 pM, from about 60 nM to about 600pM, from about 60 nM to about 500 pM, from about 60 nM to about 400 pM,from about 60 nM to about 300 pM, from about 60 nM to about 200 pM, fromabout 60 nM to about 100 pM, or less than 100 pM. In some embodiments,the dissociation constants (K_(D)) of anti-TREM2 antibodies forcynomolgus monkey TREM2 may range from about 50 nM to about 900 pM, fromabout 50 nM to about 800 pM, from about 50 nM to about 700 pM, fromabout 50 nM to about 600 pM, from about 50 nM to about 500 pM, fromabout 50 nM to about 400 pM, from about 50 nM to about 300 pM, fromabout 50 nM to about 200 pM, from about 50 nM to about 100 pM, or lessthan 100 pM. In some embodiments, the dissociation constants (K_(D)) ofanti-TREM2 antibodies for cynomolgus monkey TREM2 may range from about40 nM to about 900 pM, from about 40 nM to about 800 pM, from about 40nM to about 700 pM, from about 40 nM to about 600 pM, from about 40 nMto about 500 pM, from about 40 nM to about 400 pM, from about 40 nM toabout 300 pM, from about 40 nM to about 200 pM, from about 40 nM toabout 100 pM, or less than 100 pM. In some embodiments, the dissociationconstants (K_(D)) of anti-TREM2 antibodies for cynomolgus monkey TREM2may range from about 30 nM to about 900 pM, from about 30 nM to about800 pM, from about 30 nM to about 700 pM, from about 30 nM to about 600pM, from about 30 nM to about 500 pM, from about 30 nM to about 400 pM,from about 30 nM to about 300 pM, from about 30 nM to about 200 pM, fromabout 30 nM to about 100 pM, or less than 100 pM, from about 20 nM toabout 900 pM, from about 20 nM to about 800 pM, from about 20 nM toabout 700 pM, from about 20 nM to about 600 pM, from about 20 nM toabout 500 pM, from about 20 nM to about 400 pM, from about 20 nM toabout 300 pM, from about 20 nM to about 200 pM, from about 20 nM toabout 100 pM, or less than 100 pM. In some embodiments, the dissociationconstants (K_(D)) of anti-TREM2 antibodies for cynomolgus monkey TREM2may range from about 10 nM to about 900 pM, from about 10 nM to about800 pM, from about 10 nM to about 700 pM, from about 10 nM to about 600pM, from about 10 nM to about 500 pM, from about 10 nM to about 400 pM,from about 10 nM to about 300 pM, from about 10 nM to about 200 pM, fromabout 10 nM to about 100 pM, or less than 100 pM. In some embodiments,the dissociation constants (K_(D)) of anti-TREM2 antibodies forcynomolgus monkey TREM2 may range from about 9 nM to about 900 pM, fromabout 9 nM to about 800 pM, from about 9 nM to about 700 pM, from about9 nM to about 600 pM, from about 9 nM to about 500 pM, from about 9 nMto about 400 pM, from about 9 nM to about 300 pM, from about 9 nM toabout 200 pM, from about 9 nM to about 100 pM, or less than 100 pM. Insome embodiments, the dissociation constants (K_(D)) of anti-TREM2antibodies for cynomolgus monkey TREM2 may range from about 8 nM toabout 900 pM, from about 8 nM to about 800 pM, from about 8 nM to about700 pM, from about 8 nM to about 600 pM, from about 8 nM to about 500pM, from about 8 nM to about 400 pM, from about 8 nM to about 300 pM,from about 8 nM to about 200 pM, from about 8 nM to about 100 pM, orless than 100 pM. In some embodiments, the dissociation constants(K_(D)) of anti-TREM2 antibodies for cynomolgus monkey TREM2 may rangefrom about 7 nM to about 900 pM, from about 7 nM to about 800 pM, fromabout 7 nM to about 700 pM, from about 7 nM to about 600 pM, from about7 nM to about 500 pM, from about 7 nM to about 400 pM, from about 7 nMto about 300 pM, from about 7 nM to about 200 pM, from about 7 nM toabout 100 pM, or less than 100 pM. In some embodiments, the dissociationconstants (K_(D)) of anti-TREM2 antibodies for cynomolgus monkey TREM2may range from about 6 nM to about 900 pM, from about 6 nM to about 800pM, from about 6 nM to about 700 pM, from about 6 nM to about 600 pM,from about 6 nM to about 500 pM, from about 6 nM to about 400 pM, fromabout 6 nM to about 300 pM, from about 6 nM to about 200 pM, from about6 nM to about 100 pM, or less than 100 pM. In some embodiments, thedissociation constants (K_(D)) of anti-TREM2 antibodies for cynomolgusmonkey TREM2 may range from about 5 nM to about 900 pM, from about 5 nMto about 800 pM, from about 5 nM to about 700 pM, from about 5 nM toabout 600 pM, from about 5 nM to about 500 pM, from about 5 nM to about400 pM, from about 5 nM to about 300 pM, from about 5 nM to about 200pM, from about 5 nM to about 100 pM, or less than 100 pM. In someembodiments, the dissociation constants (K_(D)) of anti-TREM2 antibodiesfor cynomolgus monkey TREM2 may range from about 4 nM to about 900 pM,from about 4 nM to about 800 pM, from about 4 nM to about 700 pM, fromabout 4 nM to about 600 pM, from about 4 nM to about 500 pM, from about4 nM to about 400 pM, from about 4 nM to about 300 pM, from about 4 nMto about 200 pM, from about 4 nM to about 100 pM, or less than 100 pM.In some embodiments, the dissociation constants (K_(D)) of anti-TREM2antibodies for cynomolgus monkey TREM2 may range from about 3 nM toabout 900 pM, from about 3 nM to about 800 pM, from about 3 nM to about700 pM, from about 3 nM to about 600 pM, from about 3 nM to about 500pM, from about 3 nM to about 400 pM, from about 3 nM to about 300 pM,from about 3 nM to about 200 pM, from about 3 nM to about 100 pM, orless than 100 pM. In some embodiments, the dissociation constants(K_(D)) of anti-TREM2 antibodies for cynomolgus monkey TREM2 may rangefrom about 2 nM to about 900 pM, from about 2 nM to about 800 pM, fromabout 2 nM to about 700 pM, from about 2 nM to about 600 pM, from about2 nM to about 500 pM, from about 2 nM to about 400 pM, from about 2 nMto about 300 pM, from about 2 nM to about 200 pM, from about 2 nM toabout 100 pM, or less than 100 pM. In some embodiments, the dissociationconstants (K_(D)) of anti-TREM2 antibodies for cynomolgus monkey TREM2may range from about 1 nM to about 900 pM, from about 1 nM to about 800pM, from about 1 nM to about 700 pM, from about 1 nM to about 600 pM,from about 1 nM to about 500 pM, from about 1 nM to about 400 pM, fromabout 1 nM to about 300 pM, from about 1 nM to about 200 pM, from about1 nM to about 100 pM, or less than 100 pM. In some embodiments, thedissociation constant (K_(D)) is determined at a temperature ofapproximately 25° C. In some embodiments, the K_(D) is determined usinga monovalent antibody (e.g., a Fab) or a full-length antibody in amonovalent form. Methods for the preparation and selection of antibodiesthat interact and/or bind with specificity to TREM2 are describedherein. (e.g., see Examples 1 and 2).

In some embodiments, the dissociation constants (K_(D)) of anti-TREM2antibodies for cynomolgus monkey TREM2 may be less than 6 μM, may beless than 5 μM, may be less than 4.6 μM, may be less than 4 μM, may beless than 3 μM, may be less than 2 μM, may be less than 1.5 μM, may beless than 1 μM, may be less than 900 nM, may be less than 800 nM, may beless than 700 nM, may be less than 600 nM, may be less than 500 nM, maybe less than 400 nM, may be less than 300 nM, may be less than 200 nM,may be less than 100 nM, may be less than 95 nM, may be less than 90 nM,may be less than 85 nM, may be less than 80 nM, may be less than 75 nM,may be less than 70 nM, may be less than 65 nM, may be less than 60 nM,may be less than 55 nM, may be less than 50 nM, may be less than 45 nM,may be less than 40 nM, may be less than 36 nM, may be less than 35 nM,may be less than 31 nM, may be less than 30 nM, may be less than 29 nM,may be less than 28 nM, may be less than 27 nM, may be less than 26 nM,may be less than 25 nM, may be less than 24 nM, may be less than 23 nM,may be less than 22 nM, may be less than 21 nM, may be less than 20 nM,may be less than 19 nM, may be less than 18.5 nM, may be less than 18nM, may be less than, may be 17 nM, may be than 16.5 nM, may be lessthan 16 nM, may be less than 15.5 nM, may be less than 15 nM, may beless than 14.5 nM, may be less than 14 nM, may be less than 13 nM, maybe less than 12 nM, may be less than 11 nM, may be less than 10 nM, maybe less than 9.5 nM, may be less than 9 nM, may be less than 8.5 nM, maybe less than 8 nM, may be less than 7.5 nM, may be less than 7 nM, maybe less than 6.5 nM, may be less than 6 nM, may be less than 5.5 nM, maybe less than 5 nM, may be less than 4.5 nM, may be less than 4 nM, maybe less than 3.5 nM, may be less than 3 nM, may be less than 2.5 nM, maybe less than 2 nM, may be less than 1.5 nM, may be less than 1 nM, maybe less than 950 pM, may be less than 900 pM, may be less than 890 pM,may be less than 850 pM, may be less than 800 pM, may be less than 750pM, may be less than 700 pM, may be less than 650 pM, may be less than600 pM, may be less than 550 pM, may be less than 500 pM, may be lessthan 450 pM, may be less than 400 pM, may be less than 375 pM, may beless than 350 pM, may be less than 325 pM, may be less than 300 pM, maybe less than 270 pM, may be less than 250 pM, may be less than 225 pM,may be less than 200 pM, may be less than 150 pM, or may be less than100 pM. In some embodiments, the dissociation constant (K_(D)) isdetermined at a temperature of approximately 25° C. In some embodiments,the K_(D) is determined using a monovalent antibody (e.g., a Fab) or afull-length antibody in a monovalent form. Methods for the preparationand selection of antibodies that interact and/or bind with specificityto TREM2 are described herein. (e.g., see Examples 1 and 2).

Dissociation constants may be determined through any analyticaltechnique, including any biochemical or biophysical technique such asELISA, surface plasmon resonance (SPR), bio-layer interferometry (see,e.g., Octet System by ForteBio), isothermal titration calorimetry (ITC),differential scanning calorimetry (DSC), circular dichroism (CD),stopped-flow analysis, and colorimetric or fluorescent protein meltinganalyses. In some embodiments, the dissociation constant (K_(D)) forTREM2 is determined at a temperature of approximately 25° C. In someembodiments, the K_(D) is determined using a monovalent antibody (e.g.,a Fab) or a full-length antibody. In some embodiments, the K_(D) isdetermined using a full-length antibody in a monovalent form. Utilizing,for example, any assay described herein (see, e.g., Examples 1 and 2).

Additional anti-TREM2 antibodies, e.g., antibodies that specificallybind to a TREM2 protein of the present disclosure, may be identified,screened, and/or characterized for their physical/chemical propertiesand/or biological activities by various assays known in the art.

Bispecific Antibodies

Certain aspects of the present disclosure relate to bispecificantibodies that bind to a TREM2 protein of the present disclosure and asecond antigen. Methods of generating bispecific antibodies are wellknown in the art and described herein. In some embodiments, bispecificantibodies of the present disclosure bind to one or more amino acidresidues of human TREM2 (SEQ ID NO: 1), or amino acid residues on aTREM2 protein corresponding to amino acid residues of SEQ ID NO: 1. Inother embodiments, bispecific antibodies of the present disclosure alsobind to one or more amino acid residues of human DAP12.

In some embodiments, bispecific antibodies of the present disclosurerecognize a first antigen and a second antigen. In some embodiments, thefirst antigen is human TREM2 or a naturally occurring variant thereof,or human DAP12 or a naturally occurring variant thereof. In someembodiments, the second antigen is a) an antigen facilitating transportacross the blood-brain-barrier; (b) an antigen facilitating transportacross the blood-brain-barrier selected from transferrin receptor (TR),insulin receptor (HIR), insulin-like growth factor receptor (IGFR),low-density lipoprotein receptor related proteins 1 and 2 (LPR-1 and 2),diphtheria toxin receptor, CRM197, a llama single domain antibody, TMEM30(A), a protein transduction domain, TAT, Syn-B, penetratin, apoly-arginine peptide, an angiopep peptide, and ANG1005; (c) adisease-causing protein selected from amyloid beta, oligomeric amyloidbeta, amyloid beta plaques, amyloid precursor protein or fragmentsthereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72(chromosome 9 open reading frame 72), c9RAN protein, prion protein,PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1,ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrialnatriuretic factor, islet amyloid polypeptide, insulin, apolipoproteinAI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin lightchain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translationproducts, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeatpeptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR)repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, andproline-arginine (PR) repeat peptides; and (d) ligands and/or proteinsexpressed on immune cells, wherein the ligands and/or proteins selectedfrom CD40, OX40, ICOS, CD28, CD137/4-1BB, CD27, GITR, PD-L1, CTLA-4,PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GAL9, TIM3, A2AR, LAG-3, andphosphatidylserine; and (e) a protein, lipid, polysaccharide, orglycolipid expressed on one or more tumor cells and any combinationthereof.

Antibody Fragments

Certain aspects of the present disclosure relate to antibody fragmentsthat bind to one or more of human TREM2, a naturally occurring variantof human TREM2, and a disease variant of human TREM2. In someembodiments, the antibody fragment is an Fab, Fab′, Fab′-SH, F(ab′)2, Fvor scFv fragment. In some embodiments, the antibody fragment is used incombination with one or more antibodies that specifically bind adisease-causing protein selected from: a) an antigen facilitatingtransport across the blood-brain-barrier; (b) an antigen facilitatingtransport across the blood-brain-barrier selected from transferrinreceptor (TR), insulin receptor (HIR), insulin-like growth factorreceptor (IGFR), low-density lipoprotein receptor related proteins 1 and2 (LPR-1 and 2), diphtheria toxin receptor, CRM197, a llama singledomain antibody, TMEM 30(A), a protein transduction domain, TAT, Syn-B,penetratin, a poly-arginine peptide, an angiopep peptide, and ANG1005;(c) a disease-causing protein selected from amyloid beta, oligomericamyloid beta, amyloid beta plaques, amyloid precursor protein orfragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein,C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prionprotein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin,ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body,atrial natriuretic factor, islet amyloid polypeptide, insulin,apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin,lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin,immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG(RAN) translation products, DiPeptide repeat (DPR) peptides,glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeatpeptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA)repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides;and (d) ligands and/or proteins expressed on immune cells, wherein theligands and/or proteins selected from CD40, OX40, ICOS, CD28,CD137/4-1BB, CD27, GITR, PD-L1, CTLA-4, PD-L2, PD-1, B7-H3, B7-H4, HVEM,BTLA, KIR, GAL9, TIM3, A2AR, LAG-3, and phosphatidylserine; and (e) aprotein, lipid, polysaccharide, or glycolipid expressed on one or moretumor cells, and any combination thereof.

Antibody Frameworks

Any of the antibodies described herein further include a framework. Insome embodiments, the framework is a human immunoglobulin framework. Forexample, in some embodiments, an antibody (e.g., an anti-TREM2 antibody)comprises HVRs as in any of the above embodiments and further comprisesan acceptor human framework, e.g., a human immunoglobulin framework or ahuman consensus framework. Human immunoglobulin frameworks may be partof the human antibody, or a non-human antibody may be humanized byreplacing one or more endogenous frameworks with human frameworkregion(s). Human framework regions that may be used for humanizationinclude but are not limited to: framework regions selected using the“best-fit” method (see, e.g., Sims et al. J. Immunol. 151:2296 (1993));framework regions derived from the consensus sequence of humanantibodies of a particular subgroup of light or heavy chain variableregions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285(1992); and Presta et al. J. Immunol., 151:2623 (1993)); human mature(somatically mutated) framework regions or human germline frameworkregions (see, e.g., Almagro and Fransson, Front. Biosci. 13:1619-1633(2008)); and framework regions derived from screening FR libraries (see,e.g., Baca et al., J. Biol. Chem. 272:10678-10684 (1997) and Rosok etal., J. Biol. Chem. 271:22611-22618 (1996)).

In some embodiments, an antibody comprises a heavy chain variable regioncomprising an HVR-H1, an HVR-H2, and an HVR-H3 of the present disclosureand one, two, three or four of the heavy chain framework regions asshown in Tables 4A to 4D. In some embodiments, an antibody comprises alight chain variable region comprising an HVR-L1, an HVR-L2, and anHVR-L3 of the present disclosure and one, two, three or four of thelight chain framework regions as shown in Tables 5A to 5D. In someembodiments, an antibody comprises a heavy chain variable regioncomprising an HVR-H1, an HVR-H2, and an HVR-H3 of the present disclosureand one, two, three or four of the heavy chain framework regions asshown in Tables 4A to 4D and further comprises a light chain variableregion comprising an HVR-L1, an HVR-L2, and an HVR-L3 of the presentdisclosure and one, two, three or four of the light chain frameworkregions as shown in Tables 5A to 5D.

Modulated Expression of Pro-Inflammatory Mediators

In some embodiments, the anti-TREM2 antibodies of the present disclosuremay modulate (e.g., increase or decrease) the expression ofpro-inflammatory mediators after binding to a TREM2 protein expressed ina cell.

As used herein, pro-inflammatory mediators are proteins involved eitherdirectly or indirectly (e.g., by way of pro-inflammatory signalingpathways) in a mechanism that induces, activates, promotes, or otherwiseincreases an inflammatory response. Any method known in the art foridentifying and characterizing pro-inflammatory mediators may be used.Examples of pro-inflammatory mediators include, without limitation,cytokines such as IFN-β, IL-1α, IL-1β, TNF-α, IL-6, IL-8, CRP, CD86,MCP-1/CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, IL-20 familymembers, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF-1, OPN, CD11c, GM-CSF,IL-11, IL-12, IL-17, IL-18, and IL-23.

In some embodiments, the anti-TREM2 antibodies of the present disclosuremay modulate functional expression and/or secretion of pro-inflammatorymediators, such as FN-β, IL-1α, IL-1β, CD86, TNF-α, IL-6, IL-8, CRP,MCP-1/CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3, IL-20 familymembers, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF1, OPN, CD11c, GM-CSF,IL-11, IL-12, IL-17, IL-18, and IL-23. In certain embodiments, modulatedexpression of the pro-inflammatory mediators occurs in macrophages,dendritic cells, monocytes, osteoclasts, Langerhans cells of skin,Kupffer cells, and/or microglial cells. Modulated expression mayinclude, without limitation, modulated gene expression, modulatedtranscriptional expression, or modulated protein expression. Any methodknown in the art for determining gene, transcript (e.g., mRNA), and/orprotein expression may be used. For example, Northern blot analysis maybe used to determine pro-inflammatory mediator gene expression levels,RT-PCR may be used to determine the level of pro-inflammatory mediatortranscription, and Western blot analysis may be used to determinepro-inflammatory mediator protein levels.

In certain embodiments, pro-inflammatory mediators include inflammatorycytokines. Accordingly, in certain embodiments, the anti-TREM2antibodies of the present disclosure may modulate secretion of one ormore inflammatory cytokines. Examples of inflammatory cytokines whosesecretion may be reduced by the anti-TREM2 antibodies of the presentdisclosure include, without limitation, FN-β, IL-1α, IL-1β, CD86, TNF-α,IL-6, IL-8, CRP, MCP-1/CCL2, CCL3, CCL4, CCL5, CCR2, CXCL-10, Gata3,IL-20 family members, IL-33, LIF, IFN-gamma, OSM, CNTF, CSF1, OPN,CD11c, GM-CSF, IL-11, IL-12, IL-17, IL-18, and IL-23.

In certain embodiments, pro-inflammatory mediators include inflammatoryreceptors. Accordingly, in certain embodiments, the anti-TREM2antibodies of the present disclosure may modulate expression of one ormore inflammatory receptors. Examples of inflammatory receptors whoseexpression may be reduced by the anti-TREM2 antibodies of the presentdisclosure include, without limitation, CD86.

As used herein, a pro-inflammatory mediator may have modulatedexpression if its expression in one or more cells of a subject treatedwith an anti-TREM2 antibody of the present disclosure is modulated(e.g., increased or decreased) as compared to the expression of the samepro-inflammatory mediator expressed in one or more cells of acorresponding subject that is not treated with the anti-TREM2 antibody.In some embodiments, the anti-TREM2 antibody of the present disclosuremay modulate pro-inflammatory mediator expression in one or more cellsof a subject by at least 10%, at least 15%, at least 20%, at least 25%,at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95%, at least 100%, atleast 110%, at least 115%, at least 120%, at least 125%, at least 130%,at least 135%, at least 140%, at least 145%, at least 150%, at least160%, at least 170%, at least 180%, at least 190%, or at least 200% forexample, as compared to pro-inflammatory mediator expression in one ormore cells of a corresponding subject that is not treated with theanti-TREM2 antibody. In other embodiments, the anti-TREM2 antibody maymodulate pro-inflammatory mediator expression in one or more cells of asubject by at least 1.5 fold, at least 1.6 fold, at least 1.7 fold, atleast 1.8 fold, at least 1.9 fold, at least 2.0 fold, at least 2.1 fold,at least 2.15 fold, at least 2.2 fold, at least 2.25 fold, at least 2.3fold, at least 2.35 fold, at least 2.4 fold, at least 2.45 fold, atleast 2.5 fold, at least 2.55 fold, at least 3.0 fold, at least 3.5fold, at least 4.0 fold, at least 4.5 fold, at least 5.0 fold, at least5.5 fold, at least 6.0 fold, at least 6.5 fold, at least 7.0 fold, atleast 7.5 fold, at least 8.0 fold, at least 8.5 fold, at least 9.0 fold,at least 9.5 fold, or at least 10 fold, for example, as compared topro-inflammatory mediator expression in one or more cells of acorresponding subject that is not treated with the anti-TREM2 antibody.

In some embodiments, anti-TREM2 antibodies of the present disclosure maybe useful for preventing, lowering the risk of, or treating conditionsand/or diseases associated with abnormal levels of one or morepro-inflammatory mediators, including dementia, frontotemporal dementia,Alzheimer's disease, vascular dementia, mixed dementia,Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophiclateral sclerosis, Huntington's disease, tauopathy disease, Nasu-Hakoladisease, stroke, acute trauma, chronic trauma, cognitive deficit, memoryloss, lupus, acute and chronic colitis, rheumatoid arthritis, woundhealing, Crohn's disease, inflammatory bowel disease, ulcerativecolitis, obesity, malaria, essential tremor, central nervous systemlupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies,multiple system atrophy, Shy-Drager syndrome, progressive supranuclearpalsy, cortical basal ganglionic degeneration, acute disseminatedencephalomyelitis, granulomartous disorders, sarcoidosis, diseases ofaging, seizures, spinal cord injury, traumatic brain injury, age relatedmacular degeneration, glaucoma, retinitis pigmentosa, retinaldegeneration, respiratory tract infection, sepsis, eye infection,systemic infection, lupus, arthritis, multiple sclerosis, low bonedensity, osteoporosis, osteogenesis, osteopetrotic disease, Paget'sdisease of bone, cancer, bladder cancer, brain cancer, breast cancer,colon cancer, rectal cancer, endometrial cancer, kidney cancer, renalcell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma,non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovariancancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), multiple myeloma, polycythemia vera, essentialthrombocytosis, primary or idiopathic myelofibrosis, primary oridiopathic myelosclerosis, myeloid-derived tumors, tumors that expressTREM2, thyroid cancer, infections, CNS herpes, parasitic infections,Trypanosome infection, Cruzi infection, Pseudomonas aeruginosainfection, Leishmania donovani infection, group B Streptococcusinfection, Campylobacter jejuni infection, Neisseria meningiditisinfection, type I HIV, and Haemophilus influenza, comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of an agent that does not inhibit interaction betweenTREM2 and one or more TREM2 ligands, and/or enhance one or moreactivities of at least one TREM2 ligand. Other aspects of the presentdisclosure relate to an agent that does not inhibit interaction betweenTREM2 and one or more TREM2 ligands, and/or enhance one or moreactivities of at least one TREM2 ligand, for use in preventing, reducingrisk, or treating a disease, disorder, or injury selected from dementia,frontotemporal dementia, Alzheimer's disease, vascular dementia, mixeddementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus,amyotrophic lateral sclerosis, Huntington's disease, tauopathy disease,Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitivedeficit, memory loss, lupus, acute and chronic colitis, rheumatoidarthritis, wound healing, Crohn's disease, inflammatory bowel disease,ulcerative colitis, obesity, malaria, essential tremor, central nervoussystem lupus, Behcet's disease, Parkinson's disease, dementia with Lewybodies, multiple system atrophy, Shy-Drager syndrome, progressivesupranuclear palsy, cortical basal ganglionic degeneration, acutedisseminated encephalomyelitis, granulomartous disorders, sarcoidosis,diseases of aging, seizures, spinal cord injury, traumatic brain injury,age related macular degeneration, glaucoma, retinitis pigmentosa,retinal degeneration, respiratory tract infection, sepsis, eyeinfection, systemic infection, lupus, arthritis, multiple sclerosis, lowbone density, osteoporosis, osteogenesis, osteopetrotic disease, Paget'sdisease of bone, cancer, bladder cancer, brain cancer, breast cancer,colon cancer, rectal cancer, endometrial cancer, kidney cancer, renalcell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma,non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovariancancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), multiple myeloma, polycythemia vera, essentialthrombocytosis, primary or idiopathic myelofibrosis, primary oridiopathic myelosclerosis, myeloid-derived tumors, tumors that expressTREM2, thyroid cancer, infections, CNS herpes, parasitic infections,Trypanosome infection, Cruzi infection, Pseudomonas aeruginosainfection, Leishmania donovani infection, group B Streptococcusinfection, Campylobacter jejuni infection, Neisseria meningiditisinfection, type I HIV, and Haemophilus influenza.

Syk Phosphorylation

In some embodiments, the anti-TREM2 antibodies of the present disclosuremay induce spleen tyrosine kinase (Syk) phosphorylation after binding toa TREM2 protein expressed in a cell.

Spleen tyrosine kinase (Syk) is an intracellular signaling molecule thatfunctions downstream of TREM2 by phosphorylating several substrates,thereby facilitating the formation of a signaling complex leading tocellular activation and inflammatory processes.

In some embodiments, anti-TREM2 antibodies of the present disclosure maybe beneficial for preventing, lowering the risk of, or treatingconditions and/or diseases associated with decreased levels of Sykphosphorylation, including dementia, frontotemporal dementia,Alzheimer's disease, vascular dementia, mixed dementia,Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophiclateral sclerosis, Huntington's disease, tauopathy disease, Nasu-Hakoladisease, stroke, acute trauma, chronic trauma, cognitive deficit, memoryloss, lupus, acute and chronic colitis, rheumatoid arthritis, woundhealing, Crohn's disease, inflammatory bowel disease, ulcerativecolitis, obesity, malaria, essential tremor, central nervous systemlupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies,multiple system atrophy, Shy-Drager syndrome, progressive supranuclearpalsy, cortical basal ganglionic degeneration, acute disseminatedencephalomyelitis, granulomartous disorders, sarcoidosis, diseases ofaging, seizures, spinal cord injury, traumatic brain injury, age relatedmacular degeneration, glaucoma, retinitis pigmentosa, retinaldegeneration, respiratory tract infection, sepsis, eye infection,systemic infection, lupus, arthritis, multiple sclerosis, low bonedensity, osteoporosis, osteogenesis, osteopetrotic disease, Paget'sdisease of bone, cancer, bladder cancer, brain cancer, breast cancer,colon cancer, rectal cancer, endometrial cancer, kidney cancer, renalcell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma,non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovariancancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), multiple myeloma, polycythemia vera, essentialthrombocytosis, primary or idiopathic myelofibrosis, primary oridiopathic myelosclerosis, myeloid-derived tumors, tumors that expressTREM2, thyroid cancer, infections, CNS herpes, parasitic infections,Trypanosome infection, Cruzi infection, Pseudomonas aeruginosainfection, Leishmania donovani infection, group B Streptococcusinfection, Campylobacter jejuni infection, Neisseria meningiditisinfection, type I HIV, and Haemophilus influenza, comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of an agent that does not inhibit interaction betweenTREM2 and one or more TREM2 ligands, and/or enhance one or moreactivities of at least one TREM2 ligand. Other aspects of the presentdisclosure relate to an agent that does not inhibit interaction betweenTREM2 and one or more TREM2 ligands, and/or enhance one or moreactivities of at least one TREM2 ligand, for use in preventing, reducingrisk, or treating a disease, disorder, or injury selected from dementia,frontotemporal dementia, Alzheimer's disease, vascular dementia, mixeddementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus,amyotrophic lateral sclerosis, Huntington's disease, tauopathy disease,Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitivedeficit, memory loss, lupus, acute and chronic colitis, rheumatoidarthritis, wound healing, Crohn's disease, inflammatory bowel disease,ulcerative colitis, obesity, malaria, essential tremor, central nervoussystem lupus, Behcet's disease, Parkinson's disease, dementia with Lewybodies, multiple system atrophy, Shy-Drager syndrome, progressivesupranuclear palsy, cortical basal ganglionic degeneration, acutedisseminated encephalomyelitis, granulomartous disorders, sarcoidosis,diseases of aging, seizures, spinal cord injury, traumatic brain injury,age related macular degeneration, glaucoma, retinitis pigmentosa,retinal degeneration, respiratory tract infection, sepsis, eyeinfection, systemic infection, lupus, arthritis, multiple sclerosis, lowbone density, osteoporosis, osteogenesis, osteopetrotic disease, Paget'sdisease of bone, cancer, bladder cancer, brain cancer, breast cancer,colon cancer, rectal cancer, endometrial cancer, kidney cancer, renalcell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma,non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovariancancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), multiple myeloma, polycythemia vera, essentialthrombocytosis, primary or idiopathic myelofibrosis, primary oridiopathic myelosclerosis, myeloid-derived tumors, tumors that expressTREM2, thyroid cancer, infections, CNS herpes, parasitic infections,Trypanosome infection, Cruzi infection, Pseudomonas aeruginosainfection, Leishmania donovani infection, group B Streptococcusinfection, Campylobacter jejuni infection, Neisseria meningiditisinfection, type I HIV, and Haemophilus influenza.

DAP12 Binding and Phosphorylation

In some embodiments, the anti-TREM2 antibodies of the present disclosuremay induce binding of TREM2 to DAP12. In other embodiments, theanti-TREM2 antibodies of the present disclosure may induce DAP12phosphorylation after binding to a TREM2 protein expressed in a cell. Inother embodiments, TREM2-mediated DAP12 phosphorylation is induced byone or more SRC family tyrosine kinases. Examples of Src family tyrosinekinases include, without limitation, Src, Syk, Yes, Fyn, Fgr, Lck, Hck,Blk, Lyn, and Frk.

DAP12 is variously referred to as TYRO protein tyrosine kinase-bindingprotein, TYROBP, KARAP, and PLOSL. DAP12 is a transmembrane signalingprotein that contains an immunoreceptor tyrosine-based activation motif(ITAM) in its cytoplasmic domain. In certain embodiments, the anti-TREM2antibody may induce DAP12 phosphorylation in its ITAM motif. Any methodknown in the art for determining protein phosphorylation, such as DAP12phosphorylation, may be used.

In some embodiments, DAP12 is phosphorylated by SRC family kinases,resulting in the recruitment and activation of the Syk kinase, ZAP70kinase, or both, to a DAP12/TREM2 complex. Thus, in certain embodiments,the anti-TREM2 antibodies of the present disclosure may recruit Syk,ZAP70, or both to a DAP12/TREM2 complex. Without wishing to be bound bytheory, it is believed that anti-TREM2 a antibodies of the presentdisclosure are useful for preventing, lowering the risk of, or treatingconditions and/or diseases associated with decreased levels of DAP12activity, DAP12 phosphorylation, or recruitment of Syk, ZAP70, or bothto a DAP12/TREM2 complex, including dementia, frontotemporal dementia,Alzheimer's disease, vascular dementia, mixed dementia,Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophiclateral sclerosis, Huntington's disease, tauopathy disease, Nasu-Hakoladisease, stroke, acute trauma, chronic trauma, cognitive deficit, memoryloss, lupus, acute and chronic colitis, rheumatoid arthritis, woundhealing, Crohn's disease, inflammatory bowel disease, ulcerativecolitis, obesity, malaria, essential tremor, central nervous systemlupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies,multiple system atrophy, Shy-Drager syndrome, progressive supranuclearpalsy, cortical basal ganglionic degeneration, acute disseminatedencephalomyelitis, granulomartous disorders, sarcoidosis, diseases ofaging, seizures, spinal cord injury, traumatic brain injury, age relatedmacular degeneration, glaucoma, retinitis pigmentosa, retinaldegeneration, respiratory tract infection, sepsis, eye infection,systemic infection, lupus, arthritis, multiple sclerosis, low bonedensity, osteoporosis, osteogenesis, osteopetrotic disease, Paget'sdisease of bone, cancer, bladder cancer, brain cancer, breast cancer,colon cancer, rectal cancer, endometrial cancer, kidney cancer, renalcell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma,non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovariancancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), multiple myeloma, polycythemia vera, essentialthrombocytosis, primary or idiopathic myelofibrosis, primary oridiopathic myelosclerosis, myeloid-derived tumors, tumors that expressTREM2, thyroid cancer, infections, CNS herpes, parasitic infections,Trypanosome infection, Cruzi infection, Pseudomonas aeruginosainfection, Leishmania donovani infection, group B Streptococcusinfection, Campylobacter jejuni infection, Neisseria meningiditisinfection, type I HIV, and Haemophilus influenza, comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of an agent that does not inhibit interaction betweenTREM2 and one or more TREM2 ligands, and/or enhance one or moreactivities of one or more TREM2 ligands, Other aspects of the presentdisclosure relate to an agent does not inhibit interaction between TREM2and one or more TREM2 ligands, and/or enhance one or more activities ofone or more TREM2 ligands, use in preventing, reducing risk, or treatinga disease, disorder, or injury selected from dementia, frontotemporaldementia, Alzheimer's disease, vascular dementia, mixed dementia,Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophiclateral sclerosis, Huntington's disease, tauopathy disease, Nasu-Hakoladisease, stroke, acute trauma, chronic trauma, cognitive deficit, memoryloss, lupus, acute and chronic colitis, rheumatoid arthritis, woundhealing, Crohn's disease, inflammatory bowel disease, ulcerativecolitis, obesity, malaria, essential tremor, central nervous systemlupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies,multiple system atrophy, Shy-Drager syndrome, progressive supranuclearpalsy, cortical basal ganglionic degeneration, acute disseminatedencephalomyelitis, granulomartous disorders, sarcoidosis, diseases ofaging, seizures, spinal cord injury, traumatic brain injury, age relatedmacular degeneration, glaucoma, retinitis pigmentosa, retinaldegeneration, respiratory tract infection, sepsis, eye infection,systemic infection, lupus, arthritis, multiple sclerosis, low bonedensity, osteoporosis, osteogenesis, osteopetrotic disease, Paget'sdisease of bone, cancer, bladder cancer, brain cancer, breast cancer,colon cancer, rectal cancer, endometrial cancer, kidney cancer, renalcell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma,non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovariancancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), multiple myeloma, polycythemia vera, essentialthrombocytosis, primary or idiopathic myelofibrosis, primary oridiopathic myelosclerosis, myeloid-derived tumors, tumors that expressTREM2, thyroid cancer, infections, CNS herpes, parasitic infections,Trypanosome infection, Cruzi infection, Pseudomonas aeruginosainfection, Leishmania donovani infection, group B Streptococcusinfection, Campylobacter jejuni infection, Neisseria meningiditisinfection, type I HIV, and Haemophilus influenza.

Proliferation, Survival and Functionality of TREM2-Expressing Cells

In some embodiments, the anti-TREM2 antibodies of the present disclosuremay increase the proliferation, survival, and/or function of dendriticcells, macrophages, monocytes, osteoclasts, Langerhans cells of skin,Kupffer cells, and microglial cells (microglia) after binding to TREM2protein expressed in a cell. In some embodiments, the anti-TREM2antibodies of the present disclosure do not inhibit the growth (e.g.,proliferation and/or survival) of one or more innate immune cells.

Microglial cells are a type of glial cell that are the residentmacrophages of the brain and spinal cord, and thus act as the first andmain form of active immune defense in the central nervous system (CNS).Microglial cells constitute 20% of the total glial cell populationwithin the brain. Microglial cells are constantly scavenging the CNS forplaques, damaged neurons and infectious agents. The brain and spinalcord are considered “immune privileged” organs in that they areseparated from the rest of the body by a series of endothelial cellsknown as the blood-brain barrier, which prevents most infections fromreaching the vulnerable nervous tissue. In the case where infectiousagents are directly introduced to the brain or cross the blood-brainbarrier, microglial cells must react quickly to decrease inflammationand destroy the infectious agents before they damage the sensitiveneural tissue. Due to the unavailability of antibodies from the rest ofthe body (few antibodies are small enough to cross the blood brainbarrier), microglia must be able to recognize foreign bodies, swallowthem, and act as antigen-presenting cells activating T-cells. Since thisprocess must be done quickly to prevent potentially fatal damage,microglial cells are extremely sensitive to even small pathologicalchanges in the CNS. They achieve this sensitivity in part by havingunique potassium channels that respond to even small changes inextracellular potassium.

As used herein, macrophages of the present disclosure include, withoutlimitation, M1 macrophages, activated M1 macrophages, and M2macrophages. As used herein, microglial cells of the present disclosureinclude, without limitation, M1 microglial cells, activated M1microglial cells, and M2 microglial cells. In some embodiments,anti-TREM2 antibodies of the present disclosure may be beneficial for,lowering the risk of, or treating conditions and/or diseases associatedwith decreased proliferation or survival, of immune cells, includingdementia, frontotemporal dementia, Alzheimer's disease, vasculardementia, mixed dementia, Creutzfeldt-Jakob disease, normal pressurehydrocephalus, amyotrophic lateral sclerosis, Huntington's disease,tauopathy disease, Nasu-Hakola disease, stroke, acute trauma, chronictrauma, cognitive deficit, memory loss, lupus, acute and chroniccolitis, rheumatoid arthritis, wound healing, Crohn's disease,inflammatory bowel disease, ulcerative colitis, obesity, malaria,essential tremor, central nervous system lupus, Behcet's disease,Parkinson's disease, dementia with Lewy bodies, multiple system atrophy,Shy-Drager syndrome, progressive supranuclear palsy, cortical basalganglionic degeneration, acute disseminated encephalomyelitis,granulomartous disorders, sarcoidosis, diseases of aging, seizures,spinal cord injury, traumatic brain injury, age related maculardegeneration, glaucoma, retinitis pigmentosa, retinal degeneration,respiratory tract infection, sepsis, eye infection, systemic infection,lupus, arthritis, multiple sclerosis, low bone density, osteoporosis,osteogenesis, osteopetrotic disease, Paget's disease of bone, cancer,bladder cancer, brain cancer, breast cancer, colon cancer, rectalcancer, endometrial cancer, kidney cancer, renal cell cancer, renalpelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma,pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acutelymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chroniclymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiplemyeloma, polycythemia vera, essential thrombocytosis, primary oridiopathic myelofibrosis, primary or idiopathic myelosclerosis,myeloid-derived tumors, tumors that express TREM2, thyroid cancer,infections, CNS herpes, parasitic infections, Trypanosome infection,Cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovaniinfection, group B Streptococcus infection, Campylobacter jejuniinfection, Neisseria meningiditis infection, type I HIV, and Haemophilusinfluenza, comprising administering to an individual in need thereof atherapeutically effective amount of an agent that does not inhibitinteraction between TREM2 and one or more TREM2 ligands, and/or enhanceone or more activities of one or more TREM2 ligands. Other aspects ofthe present disclosure relate to an agent that does not inhibitinteraction between TREM2 and one or more TREM2 ligands, and/or enhanceone or more activities of one or more TREM2 ligands for use inpreventing, reducing risk, or treating a disease, disorder, or injuryselected from dementia, frontotemporal dementia, Alzheimer's disease,vascular dementia, mixed dementia, Creutzfeldt-Jakob disease, normalpressure hydrocephalus, amyotrophic lateral sclerosis, Huntington'sdisease, tauopathy disease, Nasu-Hakola disease, stroke, acute trauma,chronic trauma, cognitive deficit, memory loss, lupus, acute and chroniccolitis, rheumatoid arthritis, wound healing, Crohn's disease,inflammatory bowel disease, ulcerative colitis, obesity, malaria,essential tremor, central nervous system lupus, Behcet's disease,Parkinson's disease, dementia with Lewy bodies, multiple system atrophy,Shy-Drager syndrome, progressive supranuclear palsy, cortical basalganglionic degeneration, acute disseminated encephalomyelitis,granulomartous disorders, sarcoidosis, diseases of aging, seizures,spinal cord injury, traumatic brain injury, age related maculardegeneration, glaucoma, retinitis pigmentosa, retinal degeneration,respiratory tract infection, sepsis, eye infection, systemic infection,lupus, arthritis, multiple sclerosis, low bone density, osteoporosis,osteogenesis, osteopetrotic disease, Paget's disease of bone, cancer,bladder cancer, brain cancer, breast cancer, colon cancer, rectalcancer, endometrial cancer, kidney cancer, renal cell cancer, renalpelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma,pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, acutelymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chroniclymphocytic leukemia (CLL), chronic myeloid leukemia (CML), multiplemyeloma, polycythemia vera, essential thrombocytosis, primary oridiopathic myelofibrosis, primary or idiopathic myelosclerosis,myeloid-derived tumors, tumors that express TREM2, thyroid cancer,infections, CNS herpes, parasitic infections, Trypanosome infection,Cruzi infection, Pseudomonas aeruginosa infection, Leishmania donovaniinfection, group B Streptococcus infection, Campylobacter jejuniinfection, Neisseria meningiditis infection, type I HIV, and Haemophilusinfluenza.

In some embodiments, anti-TREM2 antibodies of the present disclosure mayincrease the expression of CD83 and/or CD86 on dendritic cells,monocytes, and/or macrophages.

As used herein, the rate of proliferation, survival, and/or function ofmacrophages, dendritic cells, monocytes, and/or microglia may includeincreased expression if the rate of proliferation, survival, and/orfunction of dendritic cells, macrophages, monocytes, osteoclasts,Langerhans cells of skin, Kupffer cells, and/or microglia in a subjecttreated with an anti-TREM2 antibody of the present disclosure is greaterthan the rate of proliferation, survival, and/or function of dendriticcells, macrophages, monocytes, osteoclasts, Langerhans cells of skin,Kupffer cells, and/or microglia in a corresponding subject that is nottreated with the anti-TREM2 antibody. In some embodiments, an anti-TREM2antibody of the present disclosure may increase the rate ofproliferation, survival, and/or function of dendritic cells,macrophages, monocytes, osteoclasts, Langerhans cells of skin, Kupffercells, and/or microglia in a subject by at least 10%, at least 15%, atleast 20%, at least 25%, at least 30%, at least 35%, at least 40%, atleast 45%, at least 50%, at least 55%, at least 60%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95%, at least 100%, at least 110%, at least 115%, at least 120%,at least 125%, at least 130%, at least 135%, at least 140%, at least145%, at least 150%, at least 160%, at least 170%, at least 180%, atleast 190%, or at least 200% for example, as compared to the rate ofproliferation, survival, and/or function of dendritic cells,macrophages, monocytes, osteoclasts, Langerhans cells of skin, Kupffercells, and/or microglia in a corresponding subject that is not treatedwith the anti-TREM2 antibody. In other embodiments, an anti-TREM2antibody of the present disclosure may increase the rate ofproliferation, survival, and/or function of dendritic cells,macrophages, monocytes, osteoclasts, Langerhans cells of skin, Kupffercells, and/or microglia in a subject by at least 1.5 fold, at least 1.6fold, at least 1.7 fold, at least 1.8 fold, at least 1.9 fold, at least2.0 fold, at least 2.1 fold, at least 2.15 fold, at least 2.2 fold, atleast 2.25 fold, at least 2.3 fold, at least 2.35 fold, at least 2.4fold, at least 2.45 fold, at least 2.5 fold, at least 2.55 fold, atleast 3.0 fold, at least 3.5 fold, at least 4.0 fold, at least 4.5 fold,at least 5.0 fold, at least 5.5 fold, at least 6.0 fold, at least 6.5fold, at least 7.0 fold, at least 7.5 fold, at least 8.0 fold, at least8.5 fold, at least 9.0 fold, at least 9.5 fold, or at least 10 fold, forexample, as compared to the rate of proliferation, survival, and/orfunction of dendritic cells, macrophages, monocytes, osteoclasts,Langerhans cells of skin, Kupffer cells, and/or microglia in acorresponding subject that is not treated with the anti-TREM2 antibody.

In some embodiments, anti-TREM2 antibodies of the present disclosure maybe beneficial for preventing, lowering the risk of, or treatingconditions and/or diseases associated with a reduction in function ofdendritic cells, macrophages, monocytes, osteoclasts, Langerhans cellsof skin, Kupffer cells, and/or microglia including dementia,frontotemporal dementia, Alzheimer's disease, vascular dementia, mixeddementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus,amyotrophic lateral sclerosis, Huntington's disease, tauopathy disease,Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitivedeficit, memory loss, lupus, acute and chronic colitis, rheumatoidarthritis, wound healing, Crohn's disease, inflammatory bowel disease,ulcerative colitis, obesity, malaria, essential tremor, central nervoussystem lupus, Behcet's disease, Parkinson's disease, dementia with Lewybodies, multiple system atrophy, Shy-Drager syndrome, progressivesupranuclear palsy, cortical basal ganglionic degeneration, acutedisseminated encephalomyelitis, granulomartous disorders, sarcoidosis,diseases of aging, seizures, spinal cord injury, traumatic brain injury,age related macular degeneration, glaucoma, retinitis pigmentosa,retinal degeneration, respiratory tract infection, sepsis, eyeinfection, systemic infection, lupus, arthritis, multiple sclerosis, lowbone density, osteoporosis, osteogenesis, osteopetrotic disease, Paget'sdisease of bone, cancer, bladder cancer, brain cancer, breast cancer,colon cancer, rectal cancer, endometrial cancer, kidney cancer, renalcell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma,non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovariancancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), multiple myeloma, polycythemia vera, essentialthrombocytosis, primary or idiopathic myelofibrosis, primary oridiopathic myelosclerosis, myeloid-derived tumors, tumors that expressTREM2, thyroid cancer, infections, CNS herpes, parasitic infections,Trypanosome infection, Cruzi infection, Pseudomonas aeruginosainfection, Leishmania donovani infection, group B Streptococcusinfection, Campylobacter jejuni infection, Neisseria meningiditisinfection, type I HIV, and Haemophilus influenza, comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of an agent that does not inhibit interaction betweenTREM2 and one or more TREM2 ligands, and/or enhance one or moreactivities of at least one TREM2 ligand. Other aspects of the presentdisclosure relate to an agent that does not inhibit interaction betweenTREM2 and one or more TREM2 ligands, and/or enhance one or moreactivities of at least one TREM2 ligand for use in preventing, reducingrisk, or treating a disease, disorder, or injury selected from dementia,frontotemporal dementia, Alzheimer's disease, vascular dementia, mixeddementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus,amyotrophic lateral sclerosis, Huntington's disease, tauopathy disease,Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitivedeficit, memory loss, lupus, acute and chronic colitis, rheumatoidarthritis, wound healing, Crohn's disease, inflammatory bowel disease,ulcerative colitis, obesity, malaria, essential tremor, central nervoussystem lupus, Behcet's disease, Parkinson's disease, dementia with Lewybodies, multiple system atrophy, Shy-Drager syndrome, progressivesupranuclear palsy, cortical basal ganglionic degeneration, acutedisseminated encephalomyelitis, granulomartous disorders, sarcoidosis,diseases of aging, seizures, spinal cord injury, traumatic brain injury,age related macular degeneration, glaucoma, retinitis pigmentosa,retinal degeneration, respiratory tract infection, sepsis, eyeinfection, systemic infection, lupus, arthritis, multiple sclerosis, lowbone density, osteoporosis, osteogenesis, osteopetrotic disease, Paget'sdisease of bone, cancer, bladder cancer, brain cancer, breast cancer,colon cancer, rectal cancer, endometrial cancer, kidney cancer, renalcell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma,non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovariancancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), multiple myeloma, polycythemia vera, essentialthrombocytosis, primary or idiopathic myelofibrosis, primary oridiopathic myelosclerosis, myeloid-derived tumors, tumors that expressTREM2, thyroid cancer, infections, CNS herpes, parasitic infections,Trypanosome infection, Cruzi infection, Pseudomonas aeruginosainfection, Leishmania donovani infection, group B Streptococcusinfection, Campylobacter jejuni infection, Neisseria meningiditisinfection, type I HIV, and Haemophilus influenza.

TREM2-Dependent Gene Expression

In some embodiments, anti-TREM2 antibodies of the present disclosure mayincrease the activity and/or expression of TREM2-dependent genes, suchas one or more transcription factors of the nuclear factor of activatedT-cells (NFAT) family of transcription factors.

In some embodiments, anti-TREM2 antibodies of the present disclosure maybe beneficial for preventing, lowering the risk of, or treatingconditions and/or diseases associated with decreased levels ofTREM2-dependent genes, including dementia, frontotemporal dementia,Alzheimer's disease, vascular dementia, mixed dementia,Creutzfeldt-Jakob disease, normal pressure hydrocephalus, amyotrophiclateral sclerosis, Huntington's disease, tauopathy disease, Nasu-Hakoladisease, stroke, acute trauma, chronic trauma, cognitive deficit, memoryloss, lupus, acute and chronic colitis, rheumatoid arthritis, woundhealing, Crohn's disease, inflammatory bowel disease, ulcerativecolitis, obesity, malaria, essential tremor, central nervous systemlupus, Behcet's disease, Parkinson's disease, dementia with Lewy bodies,multiple system atrophy, Shy-Drager syndrome, progressive supranuclearpalsy, cortical basal ganglionic degeneration, acute disseminatedencephalomyelitis, granulomartous disorders, sarcoidosis, diseases ofaging, seizures, spinal cord injury, traumatic brain injury, age relatedmacular degeneration, glaucoma, retinitis pigmentosa, retinaldegeneration, respiratory tract infection, sepsis, eye infection,systemic infection, lupus, arthritis, multiple sclerosis, low bonedensity, osteoporosis, osteogenesis, osteopetrotic disease, Paget'sdisease of bone, cancer, bladder cancer, brain cancer, breast cancer,colon cancer, rectal cancer, endometrial cancer, kidney cancer, renalcell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma,non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovariancancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), multiple myeloma, polycythemia vera, essentialthrombocytosis, primary or idiopathic myelofibrosis, primary oridiopathic myelosclerosis, myeloid-derived tumors, tumors that expressTREM2, thyroid cancer, infections, CNS herpes, parasitic infections,Trypanosome infection, Cruzi infection, Pseudomonas aeruginosainfection, Leishmania donovani infection, group B Streptococcusinfection, Campylobacter jejuni infection, Neisseria meningiditisinfection, type I HIV, and Haemophilus influenza, comprisingadministering to an individual in need thereof a therapeuticallyeffective amount of an agent that does not inhibit interaction betweenTREM2 and one or more TREM2 ligands, and/or enhance one or moreactivities of at least one TREM2 ligand. Other aspects of the presentdisclosure relate to an agent that does not inhibit interaction betweenTREM2 and one or more CD33 ligands for use in preventing, reducing risk,or treating a disease, disorder, or injury selected from dementia,frontotemporal dementia, Alzheimer's disease, vascular dementia, mixeddementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus,amyotrophic lateral sclerosis, Huntington's disease, tauopathy disease,Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitivedeficit, memory loss, lupus, acute and chronic colitis, rheumatoidarthritis, wound healing, Crohn's disease, inflammatory bowel disease,ulcerative colitis, obesity, malaria, essential tremor, central nervoussystem lupus, Behcet's disease, Parkinson's disease, dementia with Lewybodies, multiple system atrophy, Shy-Drager syndrome, progressivesupranuclear palsy, cortical basal ganglionic degeneration, acutedisseminated encephalomyelitis, granulomartous disorders, sarcoidosis,diseases of aging, seizures, spinal cord injury, traumatic brain injury,age related macular degeneration, glaucoma, retinitis pigmentosa,retinal degeneration, respiratory tract infection, sepsis, eyeinfection, systemic infection, lupus, arthritis, multiple sclerosis, lowbone density, osteoporosis, osteogenesis, osteopetrotic disease, Paget'sdisease of bone, cancer, bladder cancer, brain cancer, breast cancer,colon cancer, rectal cancer, endometrial cancer, kidney cancer, renalcell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma,non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovariancancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), multiple myeloma, polycythemia vera, essentialthrombocytosis, primary or idiopathic myelofibrosis, primary oridiopathic myelosclerosis, myeloid-derived tumors, tumors that expressTREM2, thyroid cancer, infections, CNS herpes, parasitic infections,Trypanosome infection, Cruzi infection, Pseudomonas aeruginosainfection, Leishmania donovani infection, group B Streptococcusinfection, Campylobacter jejuni infection, Neisseria meningiditisinfection, type I HIV, and Haemophilus influenza.

Antibody Preparation

Anti-TREM2 antibodies of the present disclosure can encompass polyclonalantibodies, monoclonal antibodies, humanized and chimeric antibodies,human antibodies, antibody fragments (e.g., Fab, Fab′-SH, Fv, scFv, andF(ab′)₂), bispecific and polyspecific antibodies, multivalentantibodies, library derived antibodies, antibodies having modifiedeffector functions, fusion proteins containing an antibody portion, andany other modified configuration of the immunoglobulin molecule thatincludes an antigen recognition site, such as an epitope having aminoacid residues of a TREM2 protein of the present disclosure, includingglycosylation variants of antibodies, amino acid sequence variants ofantibodies, and covalently modified antibodies. The anti-TREM2antibodies may be human, murine, rat, or of any other origin (includingchimeric or humanized antibodies).

(1) Polyclonal Antibodies

Polyclonal antibodies, such as anti-TREM2 polyclonal antibodies, aregenerally raised in animals by multiple subcutaneous (sc) orintraperitoneal (ip) injections of the relevant antigen and an adjuvant.It may be useful to conjugate the relevant antigen (e.g., a purified orrecombinant TREM2 protein of the present disclosure) to a protein thatis immunogenic in the species to be immunized, e.g., keyhole limpethemocyanin (KLH), serum albumin, bovine thyroglobulin, or soybeantrypsin inhibitor, using a bifunctional or derivatizing agent, e.g.,maleimidobenzoyl sulfosuccinimide ester (conjugation through cysteineresidues), N-hydroxysuccinimide (through lysine residues),glutaraldehyde, succinic anhydride, SOCl₂, or R¹N═C═NR, where R and R¹are independently lower alkyl groups. Examples of adjuvants which may beemployed include Freund's complete adjuvant and MPL-TDM adjuvant(monophosphoryl Lipid A, synthetic trehalose dicorynomycolate). Theimmunization protocol may be selected by one skilled in the art withoutundue experimentation.

The animals are immunized against the desired antigen, immunogenicconjugates, or derivatives by combining, e.g., 100 μg (for rabbits) or 5μg (for mice) of the protein or conjugate with 3 volumes of Freund'scomplete adjuvant and injecting the solution intradermally at multiplesites. One month later, the animals are boosted with ⅕ to 1/10 theoriginal amount of peptide or conjugate in Freund's complete adjuvant bysubcutaneous injection at multiple sites. Seven to fourteen days later,the animals are bled and the serum is assayed for antibody titer.Animals are boosted until the titer plateaus. Conjugates also can bemade in recombinant-cell culture as protein fusions. Also, aggregatingagents such as alum are suitable to enhance the immune response.

(2) Monoclonal Antibodies

Monoclonal antibodies, such as anti-TREM2 monoclonal antibodies, areobtained from a population of substantially homogeneous antibodies,i.e., the individual antibodies comprising the population are identicalexcept for possible naturally occurring mutations and/orpost-translational modifications (e.g., isomerizations, amidations) thatmay be present in minor amounts. Thus, the modifier “monoclonal”indicates the character of the antibody as not being a mixture ofdiscrete antibodies.

For example, the anti-TREM2 monoclonal antibodies may be made using thehybridoma method first described by Kohler et al., Nature, 256:495(1975), or may be made by recombinant DNA methods (U.S. Pat. No.4,816,567).

In the hybridoma method, a mouse or other appropriate host animal, suchas a hamster, is immunized as hereinabove described to elicitlymphocytes that produce or are capable of producing antibodies thatwill specifically bind to the protein used for immunization (e.g., apurified or recombinant TREM2 protein of the present disclosure).Alternatively, lymphocytes may be immunized in vitro. Lymphocytes thenare fused with myeloma cells using a suitable fusing agent, such aspolyethylene glycol, to form a hybridoma cell (Goding, MonoclonalAntibodies: Principles and Practice, pp. 59-103 (Academic Press, 1986)).

The immunizing agent will typically include the antigenic protein (e.g.,a purified or recombinant TREM2 protein of the present disclosure) or afusion variant thereof. Generally peripheral blood lymphocytes (“PBLs”)are used if cells of human origin are desired, while spleen or lymphnode cells are used if non-human mammalian sources are desired. Thelymphoctyes are then fused with an immortalized cell line using asuitable fusing agent, such as polyethylene glycol, to form a hybridomacell. Goding, Monoclonal Antibodies: Principles and Practice, AcademicPress (1986), pp. 59-103.

Immortalized cell lines are usually transformed mammalian cells,particularly myeloma cells of rodent, bovine or human origin. Usually,rat or mouse myeloma cell lines are employed. The hybridoma cells thusprepared are seeded and grown in a suitable culture medium thatpreferably contains one or more substances that inhibit the growth orsurvival of the unfused, parental myeloma cells. For example, if theparental myeloma cells lack the enzyme hypoxanthine guaninephosphoribosyl transferase (HGPRT or HPRT), the culture medium for thehybridomas typically will include hypoxanthine, aminopterin, andthymidine (HAT medium), which are substances that prevent the growth ofHGPRT-deficient-cells.

Preferred immortalized myeloma cells are those that fuse efficiently,support stable high-level production of antibody by the selectedantibody-producing cells, and are sensitive to a medium such as HATmedium. Among these, preferred are murine myeloma lines, such as thosederived from MOPC-21 and MPC-11 mouse tumors (available from the SalkInstitute Cell Distribution Center, San Diego, Calif. USA), as well asSP-2 cells and derivatives thereof (e.g., X63-Ag8-653) (available fromthe American Type Culture Collection, Manassas, Va. USA). Human myelomaand mouse-human heteromyeloma cell lines have also been described forthe production of human monoclonal antibodies (Kozbor, J. Immunol.,133:3001 (1984); Brodeur et al., Monoclonal Antibody ProductionTechniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York,1987)).

Culture medium in which hybridoma cells are growing is assayed forproduction of monoclonal antibodies directed against the antigen (e.g.,a TREM2 protein of the present disclosure). Preferably, the bindingspecificity of monoclonal antibodies produced by hybridoma cells isdetermined by immunoprecipitation or by an in vitro binding assay, suchas radioimmunoassay (RIA) or enzyme-linked immunosorbent assay (ELISA).

The culture medium in which the hybridoma cells are cultured can beassayed for the presence of monoclonal antibodies directed against thedesired antigen (e.g., a TREM2 protein of the present disclosure).Preferably, the binding affinity and specificity of the monoclonalantibody can be determined by immunoprecipitation or by an in vitrobinding assay, such as radioimmunoassay (RIA) or enzyme-linked assay(ELISA). Such techniques and assays are known in the in art. Forexample, binding affinity may be determined by the Scatchard analysis ofMunson et al., Anal. Biochem., 107:220 (1980).

After hybridoma cells are identified that produce antibodies of thedesired specificity, affinity, and/or activity, the clones may besubcloned by limiting dilution procedures and grown by standard methods(Goding, supra). Suitable culture media for this purpose include, forexample, D-MEM or RPMI-1640 medium. In addition, the hybridoma cells maybe grown in vivo as tumors in a mammal.

The monoclonal antibodies secreted by the subclones are suitablyseparated from the culture medium, ascites fluid, or serum byconventional immunoglobulin purification procedures such as, forexample, protein A-Sepharose chromatography, hydroxylapatitechromatography, gel electrophoresis, dialysis, affinity chromatography,and other methods as described above.

Anti-TREM2 monoclonal antibodies may also be made by recombinant DNAmethods, such as those disclosed in U.S. Pat. No. 4,816,567, and asdescribed above. DNA encoding the monoclonal antibodies is readilyisolated and sequenced using conventional procedures (e.g., by usingoligonucleotide probes that specifically bind to genes encoding theheavy and light chains of murine antibodies). The hybridoma cells serveas a preferred source of such DNA. Once isolated, the DNA may be placedinto expression vectors, which are then transfected into host-cells suchas E. coli cells, simian COS cells, Chinese hamster ovary (CHO) cells,or myeloma cells that do not otherwise produce immunoglobulin protein,in order to synthesize monoclonal antibodies in such recombinanthost-cells. Review articles on recombinant expression in bacteria of DNAencoding the antibody include Skerra et al., Curr. Opin. Immunol.,5:256-262 (1993) and Plückthun, Immunol. Rev. 130:151-188 (1992).

In certain embodiments, anti-TREM2 antibodies can be isolated fromantibody phage libraries generated using the techniques described inMcCafferty et al., Nature, 348:552-554 (1990). Clackson et al., Nature,352:624-628 (1991) and Marks et al., J. Mol. Biol., 222:581-597 (1991)described the isolation of murine and human antibodies, respectively,from phage libraries. Subsequent publications describe the production ofhigh affinity (nanomolar (“nM”) range) human antibodies by chainshuffling (Marks et al., Bio/Technology, 10:779-783 (1992)), as well ascombinatorial infection and in vivo recombination as a strategy forconstructing very large phage libraries (Waterhouse et al., Nucl. AcidsRes., 21:2265-2266 (1993)). Thus, these techniques are viablealternatives to traditional monoclonal antibody hybridoma techniques forisolation of monoclonal antibodies of desired specificity (e.g., thosethat bind a TREM2 protein of the present disclosure).

The DNA encoding antibodies or fragments thereof may also be modified,for example, by substituting the coding sequence for human heavy- andlight-chain constant domains in place of the homologous murine sequences(U.S. Pat. No. 4,816,567; Morrison, et al., Proc. Natl Acad. Sci. USA,81:6851 (1984)), or by covalently joining to the immunoglobulin codingsequence all or part of the coding sequence for a non-immunoglobulinpolypeptide. Typically such non-immunoglobulin polypeptides aresubstituted for the constant domains of an antibody, or they aresubstituted for the variable domains of one antigen-combining site of anantibody to create a chimeric bivalent antibody comprising oneantigen-combining site having specificity for an antigen and anotherantigen-combining site having specificity for a different antigen.

The monoclonal antibodies described herein (e.g., anti-TREM2 antibodiesof the present disclosure or fragments thereof) may by monovalent, thepreparation of which is well known in the art. For example, one methodinvolves recombinant expression of immunoglobulin light chain and amodified heavy chain. The heavy chain is truncated generally at anypoint in the Fc region so as to prevent heavy chain crosslinking.Alternatively, the relevant cysteine residues may be substituted withanother amino acid residue or are deleted so as to prevent crosslinking.In vitro methods are also suitable for preparing monovalent antibodies.Digestion of antibodies to produce fragments thereof, particularly Fabfragments, can be accomplished using routine techniques known in theart.

Chimeric or hybrid anti-TREM2 antibodies also may be prepared in vitrousing known methods in synthetic protein chemistry, including thoseinvolving crosslinking agents. For example, immunotoxins may beconstructed using a disulfide-exchange reaction or by forming athioether bond. Examples of suitable reagents for this purpose includeiminothiolate and methyl-4-mercaptobutyrimidate.

(3) Humanized Antibodies

Anti-TREM2 antibodies of the present disclosure or antibody fragmentsthereof may further include humanized or human antibodies. Humanizedforms of non-human (e.g., murine) antibodies are chimericimmunoglobulins, immunoglobulin chains or fragments thereof (such asFab, Fab′-SH, Fv, scFv, F(ab′)₂ or other antigen-binding subsequences ofantibodies) which contain minimal sequence derived from non-humanimmunoglobulin. Humanized antibodies include human immunoglobulins(recipient antibody) in which residues from a complementaritydetermining region (CDR) of the recipient are replaced by residues froma CDR of a non-human species (donor antibody) such as mouse, rat orrabbit having the desired specificity, affinity and capacity. In someinstances, Fv framework residues of the human immunoglobulin arereplaced by corresponding non-human residues. Humanized antibodies mayalso comprise residues which are found neither in the recipient antibodynor in the imported CDR or framework sequences. In general, thehumanized antibody will comprise substantially all of at least one, andtypically two, variable domains, in which all or substantially all ofthe CDR regions correspond to those of a non-human immunoglobulin andall or substantially all of the FR regions are those of a humanimmunoglobulin consensus sequence. The humanized antibody optimally willalso comprise at least a portion of an immunoglobulin constant region(Fc), typically that of a human immunoglobulin. Jones et al., Nature321: 522-525 (1986); Riechmann et al., Nature 332: 323-329 (1988) andPresta, Curr. Opin. Struct. Biol. 2: 593-596 (1992).

Methods for humanizing non-human anti-TREM2 antibodies are well known inthe art. Generally, a humanized antibody has one or more amino acidresidues introduced into it from a source which is non-human. Thesenon-human amino acid residues are often referred to as “import”residues, which are typically taken from an “import” variable domain.Humanization can be essentially performed following the method of Winterand co-workers, Jones et al., Nature 321:522-525 (1986); Riechmann etal., Nature 332:323-327 (1988); Verhoeyen et al., Science 239:1534-1536(1988), or through substituting rodent CDRs or CDR sequences for thecorresponding sequences of a human antibody. Accordingly, such“humanized” antibodies are chimeric antibodies (U.S. Pat. No.4,816,567), wherein substantially less than an intact human variabledomain has been substituted by the corresponding sequence from anon-human species. In practice, humanized antibodies are typically humanantibodies in which some CDR residues and possibly some FR residues aresubstituted by residues from analogous sites in rodent antibodies.

The choice of human variable domains, both light and heavy, to be usedin making the humanized antibodies is very important to reduceantigenicity. According to the so-called “best-fit” method, the sequenceof the variable domain of a rodent antibody is screened against theentire library of known human variable-domain sequences. The humansequence which is closest to that of the rodent is then accepted as thehuman framework (FR) for the humanized antibody. Sims et al., J.Immunol., 151:2296 (1993); Chothia et al., J. Mol. Biol., 196:901(1987). Another method uses a particular framework derived from theconsensus sequence of all human antibodies of a particular subgroup oflight or heavy chains. The same framework may be used for severaldifferent humanized antibodies. Carter et al., Proc. Nat'l Acad. Sci.USA 89:4285 (1992); Presta et al., J. Immunol. 151:2623 (1993).

Furthermore, it is important that antibodies be humanized with retentionof high affinity for the antigen and other favorable biologicalproperties. To achieve this goal, according to a preferred method,humanized antibodies are prepared by a process of analyzing the parentalsequences and various conceptual humanized products usingthree-dimensional models of the parental and humanized sequences.Three-dimensional immunoglobulin models are commonly available and arefamiliar to those skilled in the art. Computer programs are availablewhich illustrate and display probable three-dimensional conformationalstructures of selected candidate immunoglobulin sequences. Inspection ofthese displays permits analysis of the likely role of the residues inthe functioning of the candidate immunoglobulin sequence, i.e., theanalysis of residues that influence the ability of the candidateimmunoglobulin to bind its antigen. In this way, FR residues can beselected and combined from the recipient and import sequences so thatthe desired antibody characteristic, such as increased affinity for thetarget antigen or antigens (e.g., TREM2 proteins of the presentdisclosure), is achieved. In general, the CDR residues are directly andmost substantially involved in influencing antigen binding.

Various forms of the humanized anti-TREM2 antibody are contemplated. Forexample, the humanized anti-TREM2 antibody may be an antibody fragment,such as an Fab, which is optionally conjugated with one or more TREM2ligand, such as HSP60. Alternatively, the humanized anti-TREM2 antibodymay be an intact antibody, such as an intact IgG1 antibody.

(4) Antibody Fragments

In certain embodiments there are advantages to using anti-TREM2 antibodyfragments, rather than whole anti-TREM2 antibodies. In some embodiments,smaller fragment sizes allow for rapid clearance and better brainpenetration.

Various techniques have been developed for the production of antibodyfragments. Traditionally, these fragments were derived via proteolyticdigestion of intact antibodies (see, e.g., Morimoto et al., J. Biochem.Biophys. Method. 24:107-117 (1992); and Brennan et al., Science 229:81(1985)). However, these fragments can now be produced directly byrecombinant host-cells, for example, using nucleic acids encodinganti-TREM2 antibodies of the present disclosure. Fab, Fv and scFvantibody fragments can all be expressed in and secreted from E. coli,thus allowing the straightforward production of large amounts of thesefragments. Anti-TREM2 antibody fragments can also be isolated from theantibody phage libraries as discussed above. Alternatively, Fab′-SHfragments can be directly recovered from E. coli and chemically coupledto form F(ab′)₂ fragments (Carter et al., Bio/Technology 10:163-167(1992)). According to another approach, F(ab′)₂ fragments can beisolated directly from recombinant host-cell culture. Production of Faband F(ab′)₂ antibody fragments with increased in vivo half-lives aredescribed in U.S. Pat. No. 5,869,046. In other embodiments, the antibodyof choice is a single chain Fv fragment (scFv). See WO 93/16185; U.S.Pat. Nos. 5,571,894 and 5,587,458. The anti-TREM2 antibody fragment mayalso be a “linear antibody,” e.g., as described in U.S. Pat. No.5,641,870. Such linear antibody fragments may be monospecific orbispecific.

(5) Bispecific and Polyspecific Antibodies

Bispecific antibodies (BsAbs) are antibodies that have bindingspecificities for at least two different epitopes, including those onthe same or another protein (e.g., one or more TREM2 proteins of thepresent disclosure). Alternatively, one part of a BsAb can be armed tobind to the target TREM2 antigen, and another can be combined with anarm that binds to a second protein. Such antibodies can be derived fromfull-length antibodies or antibody fragments (e.g., F(ab′)₂ bispecificantibodies).

Methods for making bispecific antibodies are known in the art.Traditional production of full-length bispecific antibodies is based onthe coexpression of two immunoglobulin heavy-chain/light chain pairs,where the two chains have different specificities. Millstein et al.,Nature, 305:537-539 (1983). Because of the random assortment ofimmunoglobulin heavy and light chains, these hybridomas (quadromas)produce a potential mixture of 10 different antibody molecules, of whichonly one has the correct bispecific structure. Purification of thecorrect molecule, which is usually done by affinity chromatographysteps, is rather cumbersome, and the product yields are low. Similarprocedures are disclosed in WO 93/08829 and in Traunecker et al., EMBOJ., 10:3655-3659 (1991).

According to a different approach, antibody variable domains with thedesired binding specificities (antibody-antigen combining sites) arefused to immunoglobulin constant domain sequences. The fusion preferablyis with an immunoglobulin heavy chain constant domain, comprising atleast part of the hinge, C_(H)2, and C_(H)3 regions. It is preferred tohave the first heavy-chain constant region (C_(H)1) containing the sitenecessary for light chain binding, present in at least one of thefusions. DNAs encoding the immunoglobulin heavy chain fusions and, ifdesired, the immunoglobulin light chain, are inserted into separateexpression vectors, and are co-transfected into a suitable hostorganism. This provides for great flexibility in adjusting the mutualproportions of the three polypeptide fragments in embodiments whenunequal ratios of the three polypeptide chains used in the constructionprovide the optimum yields. It is, however, possible to insert thecoding sequences for two or all three polypeptide chains in oneexpression vector when the expression of at least two polypeptide chainsin equal ratios results in high yields or when the ratios are of noparticular significance.

In a preferred embodiment of this approach, the bispecific antibodiesare composed of a hybrid immunoglobulin heavy chain with a first bindingspecificity in one arm, and a hybrid immunoglobulin heavy chain-lightchain pair (providing a second binding specificity) in the other arm. Itwas found that this asymmetric structure facilitates the separation ofthe desired bispecific compound from unwanted immunoglobulin chaincombinations, as the presence of an immunoglobulin light chain in onlyhalf of the bispecific molecules provides for an easy way of separation.This approach is disclosed in WO 94/04690. For further details ofgenerating bispecific antibodies, see, for example, Suresh et al.,Methods in Enzymology 121: 210 (1986); and Garber, Nature Reviews DrugDiscovery 13, 799-801 (2014).

According to another approach described in WO 96/27011 or U.S. Pat. No.5,731,168, the interface between a pair of antibody molecules can beengineered to maximize the percentage of heterodimers which arerecovered from recombinant-cell culture. The preferred interfacecomprises at least a part of the C_(H)3 region of an antibody constantdomain. In this method, one or more small amino acid side chains fromthe interface of the first antibody molecule are replaced with largerside chains (e.g., tyrosine or tryptophan). Compensatory “cavities” ofidentical or similar size to the large side chains(s) are created on theinterface of the second antibody molecule by replacing large amino acidside chains with smaller ones (e.g., alanine or threonine). Thisprovides a mechanism for increasing the yield of the heterodimer overother unwanted end-products such as homodimers.

Techniques for generating bispecific antibodies from antibody fragmentshave been described in the literature. For example, bispecificantibodies can be prepared using chemical linkage. Brennan et al.,Science 229:81 (1985) describe a procedure wherein intact antibodies areproteolytically cleaved to generate F(ab′)₂ fragments. These fragmentsare reduced in the presence of the dithiol complexing agent sodiumarsenite to stabilize vicinal dithiols and prevent intermoleculardisulfide formation. The Fab′ fragments generated are then converted tothionitrobenzoate (TNB) derivatives. One of the Fab′-TNB derivatives isthen reconverted to the Fab′-TNB derivative to form the bispecificantibody. The bispecific antibodies produced can be used as agents forthe selective immobilization of enzymes.

Fab′ fragments may be directly recovered from E. coli and chemicallycoupled to form bispecific antibodies. Shalaby et al., J. Exp. Med 175:217-225 (1992) describes the production of fully humanized bispecificantibody F(ab′)₂ molecules. Each Fab′ fragment was separately secretedfrom E. coli and subjected to directed chemical coupling in vitro toform the bispecific antibody. The bispecific antibody thus formed wasable to bind to cells overexpressing the ErbB2 receptor and normal humanT-cells, as well as trigger the lytic activity of human cytotoxiclymphocytes against human breast tumor targets.

Various techniques for making and isolating bivalent antibody fragmentsdirectly from recombinant-cell culture have also been described. Forexample, bivalent heterodimers have been produced using leucine zippers.Kostelny et al., J. Immunol., 148(5):1547-1553 (1992). The leucinezipper peptides from the Fos and Jun proteins were linked to the Fab′portions of two different antibodies by gene fusion. The antibodyhomodimers were reduced at the hinge region to form monomers and thenre-oxidized to form the antibody heterodimers. The “diabody” technologydescribed by Hollinger et al., Proc. Nat'l Acad. Sci. USA, 90: 6444-6448(1993) has provided an alternative mechanism for makingbispecific/bivalent antibody fragments. The fragments comprise aheavy-chain variable domain (V_(H)) connected to a light-chain variabledomain (V_(L)) by a linker which is too short to allow pairing betweenthe two domains on the same chain. Accordingly, the V_(H) and V_(L)domains of one fragment are forced to pair with the complementary V_(L)and V_(H) domains of another fragment, thereby forming twoantigen-binding sites. Another strategy for making bispecific/bivalentantibody fragments by the use of single-chain Fv (sFv) dimers has alsobeen reported. See Gruber et al., J. Immunol., 152:5368 (1994).

Another method to generate bispecific antibodies is designatedcontrolled Fab-arm exchange (cFAE), which is an easy-to-use method togenerate bispecific IgG1 (bsIgG1). The protocol involves the following:(i) separate expression of two parental IgG1s containing single matchingpoint mutations in the CH3 domain; (ii) mixing of parental IgG1s underpermissive redox conditions in vitro to enable recombination ofhalf-molecules; (iii) removal of the reductant to allow reoxidation ofinterchain disulfide bonds; and (iv) analysis of exchange efficiency andfinal product using chromatography-based or mass spectrometry (MS)-basedmethods. The protocol generates bsAbs with regular IgG architecture,characteristics and quality attributes both at bench scale (microgramsto milligrams) and at a mini-bioreactor scale (milligrams to grams) thatis designed to model large-scale manufacturing (kilograms). Startingfrom good-quality purified proteins, exchange efficiencies of ≥95% canbe obtained within 2-3 days (including quality control). See Labrijn etal., Natur Protocols 9, 2450-2463 (2014); and Garber, Nature ReviewsDrug Discovery 13, 799-801 (2014).

Antibodies with more than two valencies are also contemplated. Forexample, trispecific antibodies can be prepared. Tutt et al., J.Immunol. 147:60 (1991).

Exemplary bispecific antibodies may bind to two different epitopes on agiven molecule (e.g., a TREM2 protein of the present disclosure). Insome embodiments a bispecific antibody binds to a first antigen, such asa TREM2 or DAP12 protein of the present disclosure, and a second antigenfacilitating transport across the blood-brain barrier. Numerous antigensare known in the art that facilitate transport across the blood-brainbarrier (see, e.g., Gabathuler R., Approaches to transport therapeuticdrugs across the blood-brain barrier to treat brain diseases, Neurobiol.Dis. 37 (2010) 48-57). Such second antigens include, without limitation,transferrin receptor (TR), insulin receptor (HIR), Insulin-like growthfactor receptor (IGFR), low-density lipoprotein receptor relatedproteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, includingCRM197 (a non-toxic mutant of diphtheria toxin), llama single domainantibodies such as TMEM 30(A) (Flippase), protein transduction domainssuch as TAT, Syn-B, or penetratin, poly-arginine or generally positivelycharged peptides, Angiopep peptides such as ANG1005 (see, e.g.,Gabathuler, 2010), and other cell surface proteins that are enriched onblood-brain barrier endothelial cells (see, e.g., Daneman et al., PLoSOne. 2010 Oct. 29; 5(10):e13741). In some embodiments, second antigensfor an anti-TREM2 antibody may include, without limitation, a DAP12antigen of the present disclosure. In other embodiments, bispecificantibodies that bind to both TREM2 and DAP12 may facilitate and enhanceone or more TREM2 activities. In other embodiments, second antigens foran anti-TREM2 antibody may include, without limitation, A beta peptide,antigen or an alpha synuclein protein antigen or, Tau protein antigenor, TDP-43 protein antigen or, prion protein antigen or, huntingtinprotein antigen, or RAN, translation Products antigen, including theDiPeptide Repeats, (DPRs peptides) composed of glycine-alanine (GA),glycine-proline (GP), glycine-arginine (GR), proline-alanine (PA), orproline-arginine (PR).

(6) Multivalent Antibodies

A multivalent antibody may be internalized (and/or catabolized) fasterthan a bivalent antibody by a cell expressing an antigen to which theantibodies bind. The anti-TREM2 antibodies of the present disclosure orantibody fragments thereof can be multivalent antibodies (which areother than of the IgM class) with three or more antigen binding sites(e.g., tetravalent antibodies), which can be readily produced byrecombinant expression of nucleic acid encoding the polypeptide chainsof the antibody. The multivalent antibody can comprise a dimerizationdomain and three or more antigen binding sites. The preferreddimerization domain comprises an Fc region or a hinge region. In thisscenario, the antibody will comprise an Fc region and three or moreantigen binding sites amino-terminal to the Fc region. The preferredmultivalent antibody herein contains three to about eight, butpreferably four, antigen binding sites. The multivalent antibodycontains at least one polypeptide chain (and preferably two polypeptidechains), wherein the polypeptide chain or chains comprise two or morevariable domains. For instance, the polypeptide chain or chains maycomprise VD1-(X1)n-VD2-(X2)n-Fc, wherein VD1 is a first variable domain,VD2 is a second variable domain, Fc is one polypeptide chain of an Fcregion, X1 and X2 represent an amino acid or polypeptide, and n is 0or 1. Similarly, the polypeptide chain or chains may compriseV_(H)-C_(H)1-flexible linker-V_(H)-C_(H)1-Fc region chain; orV_(H)-C_(H)1-V_(H)-C_(H)1-Fc region chain. The multivalent antibodyherein preferably further comprises at least two (and preferably four)light chain variable domain polypeptides. The multivalent antibodyherein may, for instance, comprise from about two to about eight lightchain variable domain polypeptides. The light chain variable domainpolypeptides contemplated here comprise a light chain variable domainand, optionally, further comprise a CL domain. The Multivalentantibodies may recognize the TREM2 antigen as well as without limitationadditional antigens A beta peptide, antigen or an alpha synucleinprotein antigen or, Tau protein antigen or, TDP-43 protein antigen or,prion protein antigen or, huntingtin protein antigen, or RAN,translation Products antigen, including the DiPeptide Repeats, (DPRspeptides) composed of glycine-alanine (GA), glycine-proline (GP),glycine-arginine (GR), proline-alanine (PA), or proline-arginine (PR),Insulin receptor, insulin like growth factor receptor. Transferrinreceptor or any other antigen that facilitate antibody transfer acrossthe blood brain barrier.

(7) Effector Function Engineering

It may also be desirable to modify an anti-TREM2 antibody of the presentdisclosure to modify effector function and/or to increase serumhalf-life of the antibody. For example, the Fc receptor binding site onthe constant region may be modified or mutated to remove or reducebinding affinity to certain Fc receptors, such as FcγRI, FcγRII, and/orFcγRIII to reduce Antibody-dependent cell-mediated cytotoxicity. In someembodiments, the effector function is impaired by removingN-glycosylation of the Fc region (e.g., in the CH 2 domain of IgG) ofthe antibody. In some embodiments, the effector function is impaired bymodifying regions such as 233-236, 297, and/or 327-331 of human IgG asdescribed in PCT WO 99/58572 and Armour et al., Molecular Immunology 40:585-593 (2003); Reddy et al., J. Immunology 164:1925-1933 (2000). Inother embodiments, it may also be desirable to modify an anti-TREM2antibody of the present disclosure to modify effector function toincrease finding selectivity toward the ITIM-containing FcgRIIb (CD32b)to increase clustering of TREM2 antibodies on adjacent cells withoutactivating humoral responses including Antibody-dependent cell-mediatedcytotoxicity and antibody-dependent cellular phagocytosis.

To increase the serum half-life of the antibody, one may incorporate asalvage receptor binding epitope into the antibody (especially anantibody fragment) as described in U.S. Pat. No. 5,739,277, for example.As used herein, the term “salvage receptor binding epitope” refers to anepitope of the Fc region of an IgG molecule (e.g., IgG₁, IgG₂, IgG₃, orIgG₄) that is responsible for increasing the in vivo serum half-life ofthe IgG molecule.

(8) Other Amino Acid Sequence Modifications

Amino acid sequence modifications of anti-TREM2 antibodies of thepresent disclosure, or antibody fragments thereof, are alsocontemplated. For example, it may be desirable to improve the bindingaffinity and/or other biological properties of the antibodies orantibody fragments. Amino acid sequence variants of the antibodies orantibody fragments are prepared by introducing appropriate nucleotidechanges into the nucleic acid encoding the antibodies or antibodyfragments, or by peptide synthesis. Such modifications include, forexample, deletions from, and/or insertions into and/or substitutions of,residues within the amino acid sequences of the antibody. Anycombination of deletion, insertion, and substitution is made to arriveat the final construct, provided that the final construct possesses thedesired characteristics (i.e., the ability to bind or physicallyinteract with a TREM2 protein of the present disclosure). The amino acidchanges also may alter post-translational processes of the antibody,such as changing the number or position of glycosylation sites.

A useful method for identification of certain residues or regions of theanti-TREM2 antibody that are preferred locations for mutagenesis iscalled “alanine scanning mutagenesis” as described by Cunningham andWells in Science, 244:1081-1085 (1989). Here, a residue or group oftarget residues are identified (e.g., charged residues such as arg, asp,his, lys, and glu) and replaced by a neutral or negatively charged aminoacid (most preferably alanine or polyalanine) to affect the interactionof the amino acids with the target antigen. Those amino acid locationsdemonstrating functional sensitivity to the substitutions then arerefined by introducing further or other variants at, or for, the sitesof substitution. Thus, while the site for introducing an amino acidsequence variation is predetermined, the nature of the mutation per seneed not be predetermined. For example, to analyze the performance of amutation at a given site, alanine scanning or random mutagenesis isconducted at the target codon or region and the expressed antibodyvariants are screened for the desired activity.

Amino acid sequence insertions include amino-(“N”) and/or carboxy-(“C”)terminal fusions ranging in length from one residue to polypeptidescontaining a hundred or more residues, as well as intrasequenceinsertions of single or multiple amino acid residues. Examples ofterminal insertions include an antibody with an N-terminal methionylresidue or the antibody fused to a cytotoxic polypeptide. Otherinsertional variants of the antibody molecule include the fusion to theN- or C-terminus of the antibody to an enzyme or a polypeptide whichincreases the serum half-life of the antibody.

Another type of variant is an amino acid substitution variant. Thesevariants have at least one amino acid residue in the antibody moleculereplaced by a different residue. The sites of greatest interest forsubstitutional mutagenesis include the hypervariable regions, but FRalterations are also contemplated. Conservative substitutions are shownin the Table C below under the heading of “preferred substitutions”. Ifsuch substitutions result in a change in biological activity, then moresubstantial changes, denominated “exemplary substitutions” in Table B,or as further described below in reference to amino acid classes, may beintroduced and the products screened.

TABLE B Amino Acid Substitutions Original Preferred Residue ExemplarySubstitutions Substitutions Ala (A) val; leu; ile val Arg (R) lys; gln;asn lys Asn (N) gln; his; asp, lys; arg gln Asp (D) glu; asn glu Cys (C)ser; ala ser Gln (Q) asn; glu asn Glu (E) asp; gln asp Gly (G) ala alaHis (H) asn; gln; lys; arg arg Ile (I) leu; val; met; ala; phe;norleucine leu Leu (L) norleucine; ile; val; met; ala; phe ile Lys (K)arg; gln; asn arg Met (M) leu; phe; ile leu Phe (F) leu; val; ile; ala;tyr tyr Pro (P) ala ala Ser (S) thr thr Thr (T) ser ser Trp (W) tyr; phetyr Tyr (Y) trp; phe; thr; ser phe Val (V) ile; leu; met; phe; ala;norleucine leu

Substantial modifications in the biological properties of the antibodyare accomplished by selecting substitutions that differ significantly intheir effect on maintaining (a) the structure of the polypeptidebackbone in the area of the substitution, for example, as a sheet orhelical conformation, (b) the charge or hydrophobicity of the moleculeat the target site, or (c) the bulk of the side chain. Naturallyoccurring residues are divided into groups based on common side-chainproperties:

(1) hydrophobic: norleucine, met, ala, val, leu, ile;

(2) neutral hydrophilic: cys, ser, thr;

(3) acidic: asp, glu;

(4) basic: asn, gln, his, lys, arg;

(5) residues that influence chain orientation: gly, pro; and

(6) aromatic: trp, tyr, phe.

Non-conservative substitutions entail exchanging a member of one ofthese classes for another class.

Any cysteine residue not involved in maintaining the proper conformationof the antibody also may be substituted, generally with serine, toimprove the oxidative stability of the molecule and prevent aberrantcrosslinking. Conversely, cysteine bond(s) may be added to the antibodyto improve its stability (particularly where the antibody is an antibodyfragment, such as an Fv fragment).

A particularly preferred type of substitutional variant involvessubstituting one or more hypervariable region residues of a parentantibody (e.g. a humanized or human anti-TREM2 antibody). Generally, theresulting variant(s) selected for further development will have improvedbiological properties relative to the parent antibody from which theyare generated. A convenient way for generating such substitutionalvariants involves affinity maturation using phage display. Briefly,several hypervariable region sites (e.g., 6-7 sites) are mutated togenerate all possible amino substitutions at each site. The antibodyvariants thus generated are displayed in a monovalent fashion fromfilamentous phage particles as fusions to the gene III product of M13packaged within each particle. The phage-displayed variants are thenscreened for their biological activity (e.g., binding affinity) asherein disclosed. In order to identify candidate hypervariable regionsites for modification, alanine scanning mutagenesis can be performed toidentify hypervariable region residues contributing significantly toantigen binding. Alternatively, or additionally, it may be beneficial toanalyze a crystal structure of the antigen-antibody complex to identifycontact points between the antibody and the antigen (e.g., a TREM2protein of the present disclosure). Such contact residues andneighboring residues are candidates for substitution according to thetechniques elaborated herein. Once such variants are generated, thepanel of variants is subjected to screening as described herein andantibodies with superior properties in one or more relevant assays maybe selected for further development. Affinity maturation may also beperformed by employing a yeast presentation technology such as thatdisclosed in, for example, WO2009/036379A2; WO2010105256; WO2012009568;and Xu et al., Protein Eng. Des. Sel., 26(10): 663-70 (2013).

Another type of amino acid variant of the antibody alters the originalglycosylation pattern of the antibody. By altering is meant deleting oneor more carbohydrate moieties found in the antibody, and/or adding oneor more glycosylation sites that are not present in the antibody.

Glycosylation of antibodies is typically either N-linked or O-linked.N-linked refers to the attachment of the carbohydrate moiety to the sidechain of an asparagine residue. The tripeptide sequencesasparagine-X-serine and asparagine-X-threonine, where X is any aminoacid except proline, are the recognition sequences for enzymaticattachment of the carbohydrate moiety to the asparagine side chain.Thus, the presence of either of these tripeptide sequences in apolypeptide creates a potential glycosylation site. O-linkedglycosylation refers to the attachment of one of the sugarsN-aceylgalactosamine, galactose, or xylose to a hydroxyamino acid, mostcommonly serine or threonine, although 5-hydroxyproline or5-hydroxylysine may also be used.

Addition of glycosylation sites to the antibody is convenientlyaccomplished by altering the amino acid sequence such that it containsone or more of the above-described tripeptide sequences (for N-linkedglycosylation sites). The alteration may also be made by the additionof, or substitution by, one or more serine or threonine residues to thesequence of the original antibody (for O-linked glycosylation sites).

Nucleic acid molecules encoding amino acid sequence variants of theanti-IgE antibody are prepared by a variety of methods known in the art.These methods include, but are not limited to, isolation from a naturalsource (in the case of naturally occurring amino acid sequence variants)or preparation by oligonucleotide-mediated (or site-directed)mutagenesis, PCR mutagenesis, and cassette mutagenesis of an earlierprepared variant or a non-variant version of the antibodies (e.g.,anti-TREM2 antibodies of the present disclosure) or antibody fragments.

(9) Other Antibody Modifications

Anti-TREM2 antibodies of the present disclosure, or antibody fragmentsthereof, can be further modified to contain additional non-proteinaceousmoieties that are known in the art and readily available, or to containdifferent types of drug conjugates that are known in the art and readilyavailable. Preferably, the moieties suitable for derivatization of theantibody are water-soluble polymers. Non-limiting examples ofwater-soluble polymers include, but are not limited to, polyethyleneglycol (PEG), copolymers of ethylene glycol/propylene glycol,carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1, 3-dioxolane, poly-1,3,6-trioxane, ethylene/maleicanhydride copolymer, polyaminoacids (either homopolymers or randomcopolymers), and dextran or poly(n-vinyl pyrrolidone)polyethyleneglycol, polypropylene glycol homopolymers, polypropylene oxide/ethyleneoxide co-polymers, polyoxyethylated polyols (e.g., glycerol), polyvinylalcohol, and mixtures thereof. Polyethylene glycol propionaldehyde mayhave advantages in manufacturing due to its stability in water. Thepolymer may be of any molecular weight, and may be branched orunbranched. The number of polymers attached to the antibody may vary,and if more than one polymer is attached, they can be the same ordifferent molecules. In general, the number and/or type of polymers usedfor derivatization can be determined based on considerations including,but not limited to, the particular properties or functions of theantibody to be improved, whether the antibody derivative will be used ina therapy under defined conditions, etc. Such techniques and othersuitable formulations are disclosed in Remington: The Science andPractice of Pharmacy, 20th Ed., Alfonso Gennaro, Ed., PhiladelphiaCollege of Pharmacy and Science (2000).

Drug conjugation involves coupling of a biological active cytotoxic(anticancer) payload or drug to an antibody that specifically targets acertain tumor marker (e.g. a protein that, ideally, is only to be foundin or on tumor cells). Antibodies track these proteins down in the bodyand attach themselves to the surface of cancer cells. The biochemicalreaction between the antibody and the target protein (antigen) triggersa signal in the tumor cell, which then absorbs or internalizes theantibody together with the cytotoxin. After the ADC is internalized, thecytotoxic drug is released and kills the cancer. Due to this targeting,ideally the drug has lower side effects and gives a wider therapeuticwindow than other chemotherapeutic agents. Technics to conjugateantibodies are disclosed are known in the art (see, e.g., Jane deLartigue, OncLive Jul. 5, 2012; ADC Review on antibody-drug conjugates;and Ducry et al., (2010). Bioconjugate Chemistry 21 (1): 5-13).

Binding Assays and Other Assays

Anti-TREM2 antibodies of the present disclosure may be tested forantigen binding activity, e.g., by known methods such as ELISA, Westernblot, etc.

In some embodiments, competition assays may be used to identify anantibody that competes with any of the antibodies listed in Tables2A-2C, 3A-3C, 4A-4D, 5A-5D, 6, and 7, or selected from AL2p-h50, AL2p-2,AL2p-3, AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10,AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18,AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26,AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77,AL2p-35, AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42,AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50,AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58,AL2p-59, AL2p-60, AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p-h22,AL2p-h23, AL2p-h24, AL2p-h25, AL2p-h26, AL2p-h27, AL2p-h28, AL2p-h29,AL2p-h30, AL2p-h31, AL2p-h32, AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36,AL2p-h42, AL2p-h43, AL2p-h44, AL2p-h47, AL2p-h59, AL2p-h76, and AL2p-h90for binding to TREM2. In certain embodiments, such a competing antibodybinds to the same epitope (e.g., a linear or a conformational epitope)that is bound by any of the antibodies listed in Tables 2A-2C, 3A-3C,4A-4D, 5A-5D, 6, and 7, or selected from AL2p-h50, AL2p-2, AL2p-3,AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11,AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19,AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27,AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35,AL2p-36, AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43,AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51,AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59,AL2p-60, AL2p-61, AL2p-62, AL2p-h19, AL2p-h21, AL2p-h22, AL2p-h23,AL2p-h24, AL2p-h25, AL2p-h26, AL2p-h27, AL2p-h28, AL2p-h29, AL2p-h30,AL2p-h31, AL2p-h32, AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36, AL2p-h42,AL2p-h43, AL2p-h44, AL2p-h47, AL2p-h59, AL2p-h76, and AL2p-h90. Detailedexemplary methods for mapping an epitope to which an antibody binds areprovided in Morris (1996) “Epitope Mapping Protocols,” in Methods inMolecular Biology vol. 66 (Humana Press, Totowa, N.J.).

In an exemplary competition assay, immobilized TREM2 or cells expressingTREM2 on cell surface are incubated in a solution comprising a firstlabeled antibody that binds to TREM2 (e.g., human or non-human primate)and a second unlabeled antibody that is being tested for its ability tocompete with the first antibody for binding to TREM2. The secondantibody may be present in a hybridoma supernatant. As a control,immobilized TREM2 or cells expressing TREM2 is incubated in a solutioncomprising the first labeled antibody but not the second unlabeledantibody. After incubation under conditions permissive for binding ofthe first antibody to TREM2, excess unbound antibody is removed, and theamount of label associated with immobilized TREM2 or cells expressingTREM2 is measured. If the amount of label associated with immobilizedTREM2 or cells expressing TREM2 is substantially reduced in the testsample relative to the control sample, then that indicates that thesecond antibody is competing with the first antibody for binding toTREM2. See Harlow and Lane (1988) Antibodies: A Laboratory Manual ch. 14(Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y.).

Nucleic Acids, Vectors, and Host Cells

Anti-TREM2 antibodies of the present disclosure may be produced usingrecombinant methods and compositions, e.g., as described in U.S. Pat.No. 4,816,567. In some embodiments, isolated nucleic acids having anucleotide sequence encoding any of the anti-TREM2 antibodies of thepresent disclosure are provided. Such nucleic acids may encode an aminoacid sequence containing the VL and/or an amino acid sequence containingthe VH of the anti-TREM2 antibody (e.g., the light and/or heavy chainsof the antibody). In some embodiments, one or more vectors (e.g.,expression vectors) containing such nucleic acids are provided. In someembodiments, a host cell containing such nucleic acid is also provided.In some embodiments, the host cell contains (e.g., has been transducedwith): (1) a vector containing a nucleic acid that encodes an amino acidsequence containing the VL of the antibody and an amino acid sequencecontaining the VH of the antibody, or (2) a first vector containing anucleic acid that encodes an amino acid sequence containing the VL ofthe antibody and a second vector containing a nucleic acid that encodesan amino acid sequence containing the VH of the antibody. In someembodiments, the host cell is eukaryotic, e.g., a Chinese Hamster Ovary(CHO) cell or lymphoid cell (e.g., Y0, NS0, Sp20 cell). Host cells ofthe present disclosure also include, without limitation, isolated cells,in vitro cultured cells, and ex vivo cultured cells.

Methods of making an anti-TREM2 antibody of the present disclosure areprovided. In some embodiments, the method includes culturing a host cellof the present disclosure containing a nucleic acid encoding theanti-TREM2 antibody, under conditions suitable for expression of theantibody. In some embodiments, the antibody is subsequently recoveredfrom the host cell (or host cell culture medium).

For recombinant production of an anti-TREM2 antibody of the presentdisclosure, a nucleic acid encoding the anti-TREM2 antibody is isolatedand inserted into one or more vectors for further cloning and/orexpression in a host cell. Such nucleic acid may be readily isolated andsequenced using conventional procedures (e.g., by using oligonucleotideprobes that are capable of binding specifically to genes encoding theheavy and light chains of the antibody).

Suitable vectors containing a nucleic acid sequence encoding any of theanti-TREM2 antibodies of the present disclosure, or fragments thereofpolypeptides (including antibodies) described herein include, withoutlimitation, cloning vectors and expression vectors. Suitable cloningvectors can be constructed according to standard techniques, or may beselected from a large number of cloning vectors available in the art.While the cloning vector selected may vary according to the host cellintended to be used, useful cloning vectors generally have the abilityto self-replicate, may possess a single target for a particularrestriction endonuclease, and/or may carry genes for a marker that canbe used in selecting clones containing the vector. Suitable examplesinclude plasmids and bacterial viruses, e.g., pUC18, pUC19, Bluescript(e.g., pBS SK+) and its derivatives, mp18, mp19, pBR322, pMB9, ColE1,pCR1, RP4, phage DNAs, and shuttle vectors such as pSA3 and pAT28. Theseand many other cloning vectors are available from commercial vendorssuch as BioRad, Strategene, and Invitrogen.

Expression vectors generally are replicable polynucleotide constructsthat contain a nucleic acid of the present disclosure. The expressionvector may replicable in the host cells either as episomes or as anintegral part of the chromosomal DNA. Suitable expression vectorsinclude but are not limited to plasmids, viral vectors, includingadenoviruses, adeno-associated viruses, retroviruses, cosmids, andexpression vector(s) disclosed in PCT Publication No. WO 87/04462.Vector components may generally include, but are not limited to, one ormore of the following: a signal sequence; an origin of replication; oneor more marker genes; suitable transcriptional controlling elements(such as promoters, enhancers and terminator). For expression (i.e.,translation), one or more translational controlling elements are alsousually required, such as ribosome binding sites, translation initiationsites, and stop codons.

The vectors containing the nucleic acids of interest can be introducedinto the host cell by any of a number of appropriate means, includingelectroporation, transfection employing calcium chloride, rubidiumchloride, calcium phosphate, DEAE-dextran, or other substances;microprojectile bombardment; lipofection; and infection (e.g., where thevector is an infectious agent such as vaccinia virus). The choice ofintroducing vectors or polynucleotides will often depend on features ofthe host cell. In some embodiments, the vector contains a nucleic acidcontaining one or more amino acid sequences encoding an anti-TREM2antibody of the present disclosure.

Suitable host cells for cloning or expression of antibody-encodingvectors include prokaryotic or eukaryotic cells. For example, anti-TREM2antibodies of the present disclosure may be produced in bacteria, inparticular when glycosylation and Fc effector function are not needed.For expression of antibody fragments and polypeptides in bacteria (e.g.,U.S. Pat. Nos. 5,648,237, 5,789,199, and 5,840,523; and Charlton,Methods in Molecular Biology, Vol. 248 (B. K. C. Lo, ed., Humana Press,Totowa, N.J., 2003), pp. 245-254, describing expression of antibodyfragments in E. coli). After expression, the antibody may be isolatedfrom the bacterial cell paste in a soluble fraction and can be furtherpurified.

In addition to prokaryotes, eukaryotic microorganisms, such asfilamentous fungi or yeast, are also suitable cloning or expressionhosts for antibody-encoding vectors, including fungi and yeast strainswhose glycosylation pathways have been “humanized,” resulting in theproduction of an antibody with a partially or fully human glycosylationpattern (e.g., Gerngross, Nat. Biotech. 22:1409-1414 (2004); and Li etal., Nat. Biotech. 24:210-215 (2006)).

Suitable host cells for the expression of glycosylated antibody can alsobe derived from multicellular organisms (invertebrates and vertebrates).Examples of invertebrate cells include plant and insect cells. Numerousbaculoviral strains have been identified which may be used inconjunction with insect cells, particularly for transfection ofSpodoptera frugiperda cells. Plant cell cultures can also be utilized ashosts (e.g., U.S. Pat. Nos. 5,959,177, 6,040,498, 6,420,548, 7,125,978,and 6,417,429, describing PLANTIBODIES™ technology for producingantibodies in transgenic plants.).

Vertebrate cells may also be used as hosts. For example, mammalian celllines that are adapted to grow in suspension may be useful. Otherexamples of useful mammalian host cell lines are monkey kidney CV1 linetransformed by SV40 (COS-7); human embryonic kidney line (293 or 293cells as described, e.g., in Graham et al., J. Gen Virol. 36:59 (1977));baby hamster kidney cells (BHK); mouse sertoli cells (TM4 cells asdescribed, e.g., in Mather, Biol. Reprod. 23:243-251 (1980)); monkeykidney cells (CV1); African green monkey kidney cells (VERO-76); humancervical carcinoma cells (HELA); canine kidney cells (MDCK; buffalo ratliver cells (BRL 3A); human lung cells (W138); human liver cells (HepG2); mouse mammary tumor (MMT 060562); TRI cells, as described, e.g., inMather et al., Annals N.Y. Acad Sci. 383:44-68 (1982); MRC 5 cells; andFS4 cells. Other useful mammalian host cell lines include Chinesehamster ovary (CHO) cells, including DHFR-CHO cells (Urlaub et al.,Proc. Natl. Acad. Sci. USA 77:4216 (1980)); and myeloma cell lines suchas Y0, NS0 and Sp2/0. For a review of certain mammalian host cell linessuitable for antibody production, see, e.g., Yazaki and Wu, Methods inMolecular Biology, Vol. 248 (B. K. C. Lo, ed., Humana Press, Totowa,N.J.), pp. 255-268 (2003).

Pharmaceutical Compositions

Anti-TREM2 antibodies of the present disclosure can be incorporated intoa variety of formulations for therapeutic administration by combiningthe antibodies with appropriate pharmaceutically acceptable carriers ordiluents, and may be formulated into preparations in solid, semi-solid,liquid or gaseous forms. Examples of such formulations include, withoutlimitation, tablets, capsules, powders, granules, ointments, solutions,suppositories, injections, inhalants, gels, microspheres, and aerosols.Pharmaceutical compositions can include, depending on the formulationdesired, pharmaceutically-acceptable, non-toxic carriers of diluents,which are vehicles commonly used to formulate pharmaceuticalcompositions for animal or human administration. The diluent is selectedso as not to affect the biological activity of the combination. Examplesof such diluents include, without limitation, distilled water, bufferedwater, physiological saline, PBS, Ringer's solution, dextrose solution,and Hank's solution. A pharmaceutical composition or formulation of thepresent disclosure can further include other carriers, adjuvants, ornon-toxic, nontherapeutic, nonimmunogenic stabilizers, excipients andthe like. The compositions can also include additional substances toapproximate physiological conditions, such as pH adjusting and bufferingagents, toxicity adjusting agents, wetting agents and detergents.

A pharmaceutical composition of the present disclosure can also includeany of a variety of stabilizing agents, such as an antioxidant forexample. When the pharmaceutical composition includes a polypeptide, thepolypeptide can be complexed with various well-known compounds thatenhance the in vivo stability of the polypeptide, or otherwise enhanceits pharmacological properties (e.g., increase the half-life of thepolypeptide, reduce its toxicity, and enhance solubility or uptake).Examples of such modifications or complexing agents include, withoutlimitation, sulfate, gluconate, citrate and phosphate. The polypeptidesof a composition can also be complexed with molecules that enhance theirin vivo attributes. Such molecules include, without limitation,carbohydrates, polyamines, amino acids, other peptides, ions (e.g.,sodium, potassium, calcium, magnesium, manganese), and lipids.

Further examples of formulations that are suitable for various types ofadministration can be found in Remington's Pharmaceutical Sciences, MacePublishing Company, Philadelphia, Pa., 17th ed. (1985). For a briefreview of methods for drug delivery, see, Langer, Science 249:1527-1533(1990).

For oral administration, the active ingredient can be administered insolid dosage forms, such as capsules, tablets, and powders, or in liquiddosage forms, such as elixirs, syrups, and suspensions. The activecomponent(s) can be encapsulated in gelatin capsules together withinactive ingredients and powdered carriers, such as glucose, lactose,sucrose, mannitol, starch, cellulose or cellulose derivatives, magnesiumstearate, stearic acid, sodium saccharin, talcum, magnesium carbonate.Examples of additional inactive ingredients that may be added to providedesirable color, taste, stability, buffering capacity, dispersion orother known desirable features are red iron oxide, silica gel, sodiumlauryl sulfate, titanium dioxide, and edible white ink. Similar diluentscan be used to make compressed tablets. Both tablets and capsules can bemanufactured as sustained release products to provide for continuousrelease of medication over a period of hours. Compressed tablets can besugar coated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric-coated for selectivedisintegration in the gastrointestinal tract. Liquid dosage forms fororal administration can contain coloring and flavoring to increasepatient acceptance.

Formulations suitable for parenteral administration include aqueous andnon-aqueous, isotonic sterile injection solutions, which can containantioxidants, buffers, bacteriostats, and solutes that render theformulation isotonic with the blood of the intended recipient, andaqueous and non-aqueous sterile suspensions that can include suspendingagents, solubilizers, thickening agents, stabilizers, and preservatives.

The components used to formulate the pharmaceutical compositions arepreferably of high purity and are substantially free of potentiallyharmful contaminants (e.g., at least National Food (NF) grade, generallyat least analytical grade, and more typically at least pharmaceuticalgrade). Moreover, compositions intended for in vivo use are usuallysterile. To the extent that a given compound must be synthesized priorto use, the resulting product is typically substantially free of anypotentially toxic agents, particularly any endotoxins, which may bepresent during the synthesis or purification process. Compositions forparental administration are also sterile, substantially isotonic andmade under GMP conditions.

Formulations may be optimized for retention and stabilization in thebrain or central nervous system. When the agent is administered into thecranial compartment, it is desirable for the agent to be retained in thecompartment, and not to diffuse or otherwise cross the blood brainbarrier. Stabilization techniques include cross-linking, multimerizing,or linking to groups such as polyethylene glycol, polyacrylamide,neutral protein carriers, etc. in order to achieve an increase inmolecular weight.

Other strategies for increasing retention include the entrapment of theantibody, such as an anti-TREM2 antibody of the present disclosure, in abiodegradable or bioerodible implant. The rate of release of thetherapeutically active agent is controlled by the rate of transportthrough the polymeric matrix, and the biodegradation of the implant. Thetransport of drug through the polymer barrier will also be affected bycompound solubility, polymer hydrophilicity, extent of polymercross-linking, expansion of the polymer upon water absorption so as tomake the polymer barrier more permeable to the drug, geometry of theimplant, and the like. The implants are of dimensions commensurate withthe size and shape of the region selected as the site of implantation.Implants may be particles, sheets, patches, plaques, fibers,microcapsules and the like and may be of any size or shape compatiblewith the selected site of insertion.

The implants may be monolithic, i.e. having the active agenthomogenously distributed through the polymeric matrix, or encapsulated,where a reservoir of active agent is encapsulated by the polymericmatrix. The selection of the polymeric composition to be employed willvary with the site of administration, the desired period of treatment,patient tolerance, the nature of the disease to be treated and the like.Characteristics of the polymers will include biodegradability at thesite of implantation, compatibility with the agent of interest, ease ofencapsulation, a half-life in the physiological environment.

Biodegradable polymeric compositions which may be employed may beorganic esters or ethers, which when degraded result in physiologicallyacceptable degradation products, including the monomers. Anhydrides,amides, orthoesters or the like, by themselves or in combination withother monomers, may find use. The polymers will be condensationpolymers. The polymers may be cross-linked or non-cross-linked. Ofparticular interest are polymers of hydroxyaliphatic carboxylic acids,either homo- or copolymers, and polysaccharides. Included among thepolyesters of interest are polymers of D-lactic acid, L-lactic acid,racemic lactic acid, glycolic acid, polycaprolactone, and combinationsthereof. By employing the L-lactate or D-lactate, a slowly biodegradingpolymer is achieved, while degradation is substantially enhanced withthe racemate. Copolymers of glycolic and lactic acid are of particularinterest, where the rate of biodegradation is controlled by the ratio ofglycolic to lactic acid. The most rapidly degraded copolymer has roughlyequal amounts of glycolic and lactic acid, where either homopolymer ismore resistant to degradation. The ratio of glycolic acid to lactic acidwill also affect the brittleness of in the implant, where a moreflexible implant is desirable for larger geometries. Among thepolysaccharides of interest are calcium alginate, and functionalizedcelluloses, particularly carboxymethylcellulose esters characterized bybeing water insoluble, a molecular weight of about 5 kD to 500 kD, etc.Biodegradable hydrogels may also be employed in the implants of thesubject invention. Hydrogels are typically a copolymer material,characterized by the ability to imbibe a liquid. Exemplary biodegradablehydrogels which may be employed are described in Heller in: Hydrogels inMedicine and Pharmacy, N. A. Peppes ed., Vol. III, CRC Press, BocaRaton, Fla., 1987, pp 137-149.

Pharmaceutical Dosages

Pharmaceutical compositions of the present disclosure containing ananti-TREM2 antibody of the present disclosure may be administered to anindividual in need of treatment with the anti-TREM2 antibody, preferablya human, in accord with known methods, such as intravenousadministration as a bolus or by continuous infusion over a period oftime, by intramuscular, intraperitoneal, intracerobrospinal,intracranial, intraspinal, subcutaneous, intra-articular, intrasynovial,intrathecal, oral, topical, or inhalation routes.

Dosages and desired drug concentration of pharmaceutical compositions ofthe present disclosure may vary depending on the particular useenvisioned. The determination of the appropriate dosage or route ofadministration is well within the skill of an ordinary artisan. Animalexperiments provide reliable guidance for the determination of effectivedoses for human therapy. Interspecies scaling of effective doses can beperformed following the principles described in Mordenti, J. andChappell, W. “The Use of Interspecies Scaling in Toxicokinetics,” InToxicokinetics and New Drug Development, Yacobi et al., Eds, PergamonPress, New York 1989, pp. 42-46.

For in vivo administration of any of the anti-TREM2 antibodies of thepresent disclosure, normal dosage amounts may vary from about 10 ng/kgup to about 100 mg/kg of an individual's body weight or more per day,preferably about 1 mg/kg/day to 10 mg/kg/day, depending upon the routeof administration. For repeated administrations over several days orlonger, depending on the severity of the disease, disorder, or conditionto be treated, the treatment is sustained until a desired suppression ofsymptoms is achieved.

An exemplary dosing regimen may include administering an initial dose ofan anti-TREM2 antibody, of about 2 mg/kg, followed by a weeklymaintenance dose of about 1 mg/kg every other week. Other dosageregimens may be useful, depending on the pattern of pharmacokineticdecay that the physician wishes to achieve. For example, dosing anindividual from one to twenty-one times a week is contemplated herein.In certain embodiments, dosing ranging from about 3 μg/kg to about 2mg/kg (such as about 3 μg/kg, about 10 μg/kg, about 30 μg/kg, about 100μg/kg, about 300 μg/kg, about 1 mg/kg, and about 2/mg/kg) may be used.In certain embodiments, dosing frequency is three times per day, twiceper day, once per day, once every other day, once weekly, once every twoweeks, once every four weeks, once every five weeks, once every sixweeks, once every seven weeks, once every eight weeks, once every nineweeks, once every ten weeks, or once monthly, once every two months,once every three months, or longer. Progress of the therapy is easilymonitored by conventional techniques and assays. The dosing regimen,including the anti-TREM2 antibody administered, can vary over timeindependently of the dose used.

Dosages for a particular anti-TREM2 antibody may be determinedempirically in individuals who have been given one or moreadministrations of the anti-TREM2 antibody. Individuals are givenincremental doses of an anti-TREM2 antibody. To assess efficacy of ananti-TREM2 antibody, a clinical symptom of any of the diseases,disorders, or conditions of the present disclosure (e.g., dementia,frontotemporal dementia, Alzheimer's disease, Nasu-Hakola disease, andmultiple sclerosis) can be monitored.

Administration of an anti-TREM2 antibody of the present disclosure canbe continuous or intermittent, depending, for example, on therecipient's physiological condition, whether the purpose of theadministration is therapeutic or prophylactic, and other factors knownto skilled practitioners. The administration of an anti-TREM2 antibodymay be essentially continuous over a preselected period of time or maybe in a series of spaced doses.

Guidance regarding particular dosages and methods of delivery isprovided in the literature; see, for example, U.S. Pat. Nos. 4,657,760;5,206,344; or 5,225,212. It is within the scope of the presentdisclosure that different formulations will be effective for differenttreatments and different disorders, and that administration intended totreat a specific organ or tissue may necessitate delivery in a mannerdifferent from that to another organ or tissue. Moreover, dosages may beadministered by one or more separate administrations, or by continuousinfusion. For repeated administrations over several days or longer,depending on the condition, the treatment is sustained until a desiredsuppression of disease symptoms occurs. However, other dosage regimensmay be useful. The progress of this therapy is easily monitored byconventional techniques and assays.

Therapeutic Uses

As disclosed herein, anti-TREM2 antibodies of the present disclosure maybe used for preventing, reducing risk, or treating dementia,frontotemporal dementia, Alzheimer's disease, vascular dementia, mixeddementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus,amyotrophic lateral sclerosis, Huntington's disease, tauopathy disease,Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitivedeficit, memory loss, lupus, acute and chronic colitis, rheumatoidarthritis, wound healing, Crohn's disease, inflammatory bowel disease,ulcerative colitis, obesity, malaria, essential tremor, central nervoussystem lupus, Behcet's disease, Parkinson's disease, dementia with Lewybodies, multiple system atrophy, Shy-Drager syndrome, progressivesupranuclear palsy, cortical basal ganglionic degeneration, acutedisseminated encephalomyelitis, granulomartous disorders, sarcoidosis,diseases of aging, seizures, spinal cord injury, traumatic brain injury,age related macular degeneration, glaucoma, retinitis pigmentosa,retinal degeneration, respiratory tract infection, sepsis, eyeinfection, systemic infection, lupus, arthritis, multiple sclerosis, lowbone density, osteoporosis, osteogenesis, osteopetrotic disease, Paget'sdisease of bone, cancer, bladder cancer, brain cancer, breast cancer,colon cancer, rectal cancer, endometrial cancer, kidney cancer, renalcell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma,non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovariancancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), multiple myeloma, polycythemia vera, essentialthrombocytosis, primary or idiopathic myelofibrosis, primary oridiopathic myelosclerosis, myeloid-derived tumors, tumors that expressTREM2, thyroid cancer, infections, CNS herpes, parasitic infections,Trypanosome infection, Cruzi infection, Pseudomonas aeruginosainfection, Leishmania donovani infection, group B Streptococcusinfection, Campylobacter jejuni infection, Neisseria meningiditisinfection, type I HIV, and/or Haemophilus influenza. In someembodiments, the anti-TREM2 antibodies are agonist antibodies.

In some embodiments, the present disclosure provides methods ofpreventing, reducing risk, or treating an individual having dementia,frontotemporal dementia, Alzheimer's disease, vascular dementia, mixeddementia, Creutzfeldt-Jakob disease, normal pressure hydrocephalus,amyotrophic lateral sclerosis, Huntington's disease, tauopathy disease,Nasu-Hakola disease, stroke, acute trauma, chronic trauma, cognitivedeficit, memory loss, lupus, acute and chronic colitis, rheumatoidarthritis, wound healing, Crohn's disease, inflammatory bowel disease,ulcerative colitis, obesity, malaria, essential tremor, central nervoussystem lupus, Behcet's disease, Parkinson's disease, dementia with Lewybodies, multiple system atrophy, Shy-Drager syndrome, progressivesupranuclear palsy, cortical basal ganglionic degeneration, acutedisseminated encephalomyelitis, granulomartous disorders, sarcoidosis,diseases of aging, seizures, spinal cord injury, traumatic brain injury,age related macular degeneration, glaucoma, retinitis pigmentosa,retinal degeneration, respiratory tract infection, sepsis, eyeinfection, systemic infection, lupus, arthritis, multiple sclerosis, lowbone density, osteoporosis, osteogenesis, osteopetrotic disease, Paget'sdisease of bone, cancer, bladder cancer, brain cancer, breast cancer,colon cancer, rectal cancer, endometrial cancer, kidney cancer, renalcell cancer, renal pelvis cancer, leukemia, lung cancer, melanoma,non-Hodgkin's lymphoma, pancreatic cancer, prostate cancer, ovariancancer, fibrosarcoma, acute lymphoblastic leukemia (ALL), acute myeloidleukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloidleukemia (CML), multiple myeloma, polycythemia vera, essentialthrombocytosis, primary or idiopathic myelofibrosis, primary oridiopathic myelosclerosis, myeloid-derived tumors, tumors that expressTREM2, thyroid cancer, infections, CNS herpes, parasitic infections,Trypanosome infection, Cruzi infection, Pseudomonas aeruginosainfection, Leishmania donovani infection, group B Streptococcusinfection, Campylobacter jejuni infection, Neisseria meningiditisinfection, type I HIV, and Haemophilus influenza, by administering tothe individual a therapeutically effective amount of an anti-TREM2antibody of the present disclosure. In some embodiments, the methodfurther includes administering to the individual at least one antibodythat specifically binds to an inhibitory checkpoint molecule, and/oranother standard or investigational anti-cancer therapy. In someembodiments, the antibody that specifically binds to an inhibitorycheckpoint molecule is administered in combination with the isolatedantibody. In some embodiments, the at least one antibody thatspecifically binds to an inhibitory checkpoint molecule is selected froman anti-PD-L1 antibody, an anti-CTLA-4 antibody, an anti-PD-L2 antibody,an anti-PD-1 antibody, an anti-B7-H3 antibody, an anti-B7-H4 antibody,and anti-HVEM antibody, an anti-B- and T-lymphocyte attenuator (BTLA)antibody, an anti-Killer inhibitory receptor (KIR) antibody, ananti-GAL9 antibody, an anti-TIM3 antibody, an anti-A2AR antibody, ananti-LAG-3 antibody, an anti-phosphatidylserine antibody, an anti-CD27antibody, and any combination thereof. In some embodiments, the standardor investigational anti-cancer therapy is one or more therapies selectedfrom radiotherapy, cytotoxic chemotherapy, targeted therapy, hormonaltherapy, imatinib (Gleevec®), trastuzumab (Herceptin®), bevacizumab(Avastin®), Ofatumumab (Arzerra®), Rituximab (Rituxan®, MabThera®,Zytux®), cryotherapy, ablation, radiofrequency ablation, adoptive celltransfer (ACT), chimeric antigen receptor T cell transfer (CAR-T),vaccine therapy, and cytokine therapy. In some embodiments, the methodfurther includes administering to the individual at least one antibodythat specifically binds to an inhibitory cytokine. In some embodiments,the at least one antibody that specifically binds to an inhibitorycytokine is administered in combination with the isolated antibody. Insome embodiments, the at least one antibody that specifically binds toan inhibitory cytokine is selected from an anti-CCL2 antibody, ananti-CSF-1 antibody, an anti-IL-2 antibody, and any combination thereof.In some embodiments, the method further includes administering to theindividual at least one agonistic antibody that specifically binds to astimulatory checkpoint protein. In some embodiments, the at least oneagonistic antibody that specifically binds to a stimulatory checkpointprotein is administered in combination with the isolated antibody. Insome embodiments, the at least one agonistic antibody that specificallybinds to a stimulatory checkpoint protein is selected from an agonistanti-CD40 antibody, an agonist anti-OX40 antibody, an agonist anti-ICOSantibody, an agonist anti-CD28 antibody, an agonist anti-CD137/4-1BBantibody, an agonist anti-CD27 antibody, an agonistanti-glucocorticoid-induced TNFR-related protein GITR antibody, and anycombination thereof. In some embodiments, the method further includesadministering to the individual at least one stimulatory cytokine. Insome embodiments, the at least one stimulatory cytokine is administeredin combination with the isolated antibody. In some embodiments, the atleast one stimulatory cytokine is selected from TNF-α, IL-10, IL-6,IL-8, CRP, TGF-beta members of the chemokine protein families, IL20family member, IL-33, LIF, OSM, CNTF, TGF-beta, IL-11, IL-12, IL-17,IL-8, IL-23, IFN-α, IFN-β, IL-2, IL-18, GM-CSF, G-CSF, and anycombination thereof.

In some embodiments, the present disclosure provides methods ofpreventing, reducing risk, or treating an individual having Alzheimer'sdisease by administering to the individual a therapeutically effectiveamount of an anti-TREM2 antibody of the present disclosure. In someembodiments, the anti-TREM2 antibody increases expression of one or moreinflammatory mediators, such as IL-1β, TNF-α, YM-1, CD86, CCL2, CCL3,CCL5, CCR2, CXCL10, Gata3, Rorc, and any combination thereof. In someembodiments, the anti-TREM2 antibody decreases expression of one or moreinflammatory mediators, such as FLT1, OPN, CSF-1, CD11c, AXL, and anycombination thereof. In some embodiments, the anti-TREM2 antibodydecreases levels of Abeta peptide in the individual (e.g., in the brainof the individual). In some embodiments, the anti-TREM2 antibodyincreases the number of CD11b⁺ microglial cells in the brain of theindividual. In some embodiments, the anti-TREM2 antibody increasesmemory in the individual. In some embodiments, the anti-TREM2 antibodyreduces cognitive deficit in the individual. In some embodiments, theanti-TREM2 antibody increases motor coordination in the individual.

In some embodiments, the present disclosure provides methods ofincreasing memory, reducing cognitive deficit, or both in an individualin need thereof, by administering to the individual a therapeuticallyeffective amount of an anti-TREM2 antibody of the present disclosure.

In some embodiments, the present disclosure provides methods ofincreasing motor coordination in an individual in need thereof, byadministering to the individual a therapeutically effective amount of ananti-TREM2 antibody of the present disclosure.

In some embodiments, the present disclosure provides methods of reducingAbeta peptide levels in an individual in need thereof, by administeringto the individual a therapeutically effective amount of an anti-TREM2antibody of the present disclosure.

In some embodiments, the present disclosure provides methods ofincreasing the number of CD11 b microglial cells in an individual inneed thereof, by administering to the individual a therapeuticallyeffective amount of an anti-TREM2 antibody of the present disclosure.

In some embodiments, the present disclosure provides methods ofincreasing levels of one or more of FLT1, OPNCSF1, CD11c, and AXL in anindividual in need thereof, by administering to the individual atherapeutically effective amount of an anti-TREM2 antibody of thepresent disclosure.

In some embodiments, an anti-TREM2 antibody of the present disclosuremay increases expression of one or more inflammatory mediators, such asIL-1β, TNF-α, YM-1, CD86, CCL2, CCL3, CCL5, CCR2, CXCL10, Gata3, Rorc,and any combination thereof in one or more cells of an individual by atleast 10%, at least 15%, at least 20%, at least 25%, at least 30%, atleast 35%, at least 40%, at least 45%, at least 50%, at least 55%, atleast 60%, at least 65%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, at least 95%, at least 100%, at least 110%, atleast 115%, at least 120%, at least 125%, at least 130%, at least 135%,at least 140%, at least 145%, at least 150%, at least 160%, at least170%, at least 180%, at least 190%, or at least 200% for example, ascompared to expression of one or more inflammatory mediators, such asIL-1β, TNF-α, YM-1, CD86, CCL2, CCL3, CCL5, CCR2, CXCL10, Gata3, Rorc,and any combination thereof in one or more cells of a correspondingindividual that is not treated with the anti-TREM2 antibody. In otherembodiments, an anti-TREM2 antibody of the present disclosure increasesexpression of one or more inflammatory mediators, such as IL-1β, TNF-α,YM-1, CD86, CCL2, CCL3, CCL5, CCR2, CXCL10, Gata3, Rorc, and anycombination thereof in one or more cells of an individual by at least1.5 fold, at least 1.6 fold, at least 1.7 fold, at least 1.8 fold, atleast 1.9 fold, at least 2.0 fold, at least 2.1 fold, at least 2.15fold, at least 2.2 fold, at least 2.25 fold, at least 2.3 fold, at least2.35 fold, at least 2.4 fold, at least 2.45 fold, at least 2.5 fold, atleast 2.55 fold, at least 3.0 fold, at least 3.5 fold, at least 4.0fold, at least 4.5 fold, at least 5.0 fold, at least 5.5 fold, at least6.0 fold, at least 6.5 fold, at least 7.0 fold, at least 7.5 fold, atleast 8.0 fold, at least 8.5 fold, at least 9.0 fold, at least 9.5 fold,or at least 10 fold, for example, as compared to expression of one ormore inflammatory mediators, such as IL-1β, TNF-α, YM-1, CD86, CCL2,CCL3, CCL5, CCR2, CXCL10, Gata3, Rorc, and any combination thereof inone or more cells of a corresponding individual that is not treated withthe anti-TREM2 antibody.

In some embodiments, an anti-TREM2 antibody of the present disclosuremay decrease expression of one or more inflammatory mediators, such asFLT1, OPN, CSF-1, CD11c, AXL, and any combination thereof in one or morecells of an individual by at least 10%, at least 15%, at least 20%, atleast 25%, at least 30%, at least 35%, at least 40%, at least 45%, atleast 50%, at least 55%, at least 60%, at least 65%, at least 70%, atleast 75%, at least 80%, at least 85%, at least 90%, at least 95%, atleast 100%, at least 110%, at least 115%, at least 120%, at least 125%,at least 130%, at least 135%, at least 140%, at least 145%, at least150%, at least 160%, at least 170%, at least 180%, at least 190%, or atleast 200% for example, as compared to expression of one or moreinflammatory mediators, such as FLT1, OPN, CSF-1, CD11c, AXL, and anycombination thereof in one or more cells of a corresponding individualthat is not treated with the anti-TREM2 antibody. In other embodiments,an anti-TREM2 antibody of the present disclosure decreases expression ofone or more inflammatory mediators, such as FLT1, OPN, CSF-1, CD11c,AXL, and any combination thereof in one or more cells of an individualby at least 1.5 fold, at least 1.6 fold, at least 1.7 fold, at least 1.8fold, at least 1.9 fold, at least 2.0 fold, at least 2.1 fold, at least2.15 fold, at least 2.2 fold, at least 2.25 fold, at least 2.3 fold, atleast 2.35 fold, at least 2.4 fold, at least 2.45 fold, at least 2.5fold, at least 2.55 fold, at least 3.0 fold, at least 3.5 fold, at least4.0 fold, at least 4.5 fold, at least 5.0 fold, at least 5.5 fold, atleast 6.0 fold, at least 6.5 fold, at least 7.0 fold, at least 7.5 fold,at least 8.0 fold, at least 8.5 fold, at least 9.0 fold, at least 9.5fold, or at least 10 fold, for example, as compared to expression of oneor more inflammatory mediators, such as FLT1, OPN, CSF-1, CD11c, AXL,and any combination thereof in one or more cells of a correspondingindividual that is not treated with the anti-TREM2 antibody.

In some embodiments, an anti-TREM2 antibody of the present disclosuremay modulate expression of one or more Stage 2 microglia type associatedwith neurodegenerative diseases (DAM) markers, such as Trem2, Cst7,Ctsl, Lpl, Cd9, Axl, Csf1, Ccl6, Itgax, Clec7a, Lilrb4, Timp2, and anycombination thereof in one or more cells of an individual by at least10%, at least 15%, at least 20%, at least 25%, at least 30%, at least35%, at least 40%, at least 45%, at least 50%, at least 55%, at least60%, at least 65%, at least 70%, at least 75%, at least 80%, at least85%, at least 90%, at least 95%, at least 100%, at least 110%, at least115%, at least 120%, at least 125%, at least 130%, at least 135%, atleast 140%, at least 145%, at least 150%, at least 160%, at least 170%,at least 180%, at least 190%, or at least 200% for example, as comparedto expression of one or more DAM markers, such as Trem2, Cst7, Ctsl,Lpl, Cd9, Axl, Csf1, Ccl6, Itgax, Clec7a, Lilrb4, Timp2, and anycombination thereof in one or more cells of a corresponding individualthat is not treated with the anti-TREM2 antibody. See Keren-Shaul et al.Cell 169:1276-1290 (2017), which is incorporated by reference in itsentirety. In other embodiments, an anti-TREM2 antibody of the presentdisclosure modulate expression of one or more DAM markers, such asTrem2, Cst7, Ctsl, Lpl, Cd9, Axl, Csf1, Ccl6, Itgax, Clec7a, Lilrb4,Timp2, and any combination thereof in one or more cells of an individualby at least 1.5 fold, at least 1.6 fold, at least 1.7 fold, at least 1.8fold, at least 1.9 fold, at least 2.0 fold, at least 2.1 fold, at least2.15 fold, at least 2.2 fold, at least 2.25 fold, at least 2.3 fold, atleast 2.35 fold, at least 2.4 fold, at least 2.45 fold, at least 2.5fold, at least 2.55 fold, at least 3.0 fold, at least 3.5 fold, at least4.0 fold, at least 4.5 fold, at least 5.0 fold, at least 5.5 fold, atleast 6.0 fold, at least 6.5 fold, at least 7.0 fold, at least 7.5 fold,at least 8.0 fold, at least 8.5 fold, at least 9.0 fold, at least 9.5fold, or at least 10 fold, for example, as compared to expression of oneor more DAM markers, such as Trem2, Cst7, Ctsl, Lpl, Cd9, Axl, Csf1,Ccl6, Itgax, Clec7a, Lilrb4, Timp2, and any combination thereof in oneor more cells of a corresponding individual that is not treated with theanti-TREM2 antibody. In some embodiments, the DAM marker is Cst7. Insome embodiments, the DAM marker is Ccl6. In some embodiments, the DAMmarker is Itgax. In some embodiments, the modulation is increasedexpression.

Further provided herein are methods of determining whether an individualis a responder or is a non-responder to an anti-TREM2 antibody treatmentwhich comprises the steps of: (a) measuring the levels of one or moreStage 2 microglia type associated with neurodegenerative diseases (DAM)markers, such as Trem2, Cst7, Ctsl, Lpl, Cd9, Axl, Csf1, Ccl6, Itgax,Clec7a, Lilrb4, Timp2, and any combination thereof in a sample from anindividual obtained from said individual before the treatment, (b)measuring the level of one or more Stage 2 microglia type associatedwith neurodegenerative diseases (DAM) markers, such as Trem2, Cst7,Ctsl, Lpl, Cd9, Axl, Csf1, Ccl6, Itgax, Clec7a, Lilrb4, Timp2, and anycombination thereof in a sample from an individual obtained from said ata time point after first treatment, and (c) comparing the levelsmeasured at step ii) with the levels measured at step i) wherein adifference between said levels is indicative that said individual is aresponder or non-responder. In some embodiments, the difference betweensaid levels is an increase and is indicative that said individual is aresponder. In some embodiments, the difference between said levels is adecrease or no change and is indicative that said individual is anon-responder. In some embodiments, the DAM marker is Cst7. In someembodiments, the DAM marker is Ccl6. In some embodiments, the DAM markeris Itgax.

In some embodiments, an anti-TREM2 antibody of the present disclosuremay decrease levels of Abeta peptide in one or more cells of anindividual by at least 10%, at least 15%, at least 20%, at least 25%, atleast 30%, at least 35%, at least 40%, at least 45%, at least 50%, atleast 55%, at least 60%, at least 65%, at least 70%, at least 75%, atleast 80%, at least 85%, at least 90%, at least 95%, at least 100%, atleast 110%, at least 115%, at least 120%, at least 125%, at least 130%,at least 135%, at least 140%, at least 145%, at least 150%, at least160%, at least 170%, at least 180%, at least 190%, or at least 200% forexample, as compared to levels of Abeta peptide in one or more cells ofa corresponding individual that is not treated with the anti-TREM2antibody. In other embodiments, an anti-TREM2 antibody of the presentdisclosure decreases levels of Abeta peptide in one or more cells of anindividual by at least 1.5 fold, at least 1.6 fold, at least 1.7 fold,at least 1.8 fold, at least 1.9 fold, at least 2.0 fold, at least 2.1fold, at least 2.15 fold, at least 2.2 fold, at least 2.25 fold, atleast 2.3 fold, at least 2.35 fold, at least 2.4 fold, at least 2.45fold, at least 2.5 fold, at least 2.55 fold, at least 3.0 fold, at least3.5 fold, at least 4.0 fold, at least 4.5 fold, at least 5.0 fold, atleast 5.5 fold, at least 6.0 fold, at least 6.5 fold, at least 7.0 fold,at least 7.5 fold, at least 8.0 fold, at least 8.5 fold, at least 9.0fold, at least 9.5 fold, or at least 10 fold, for example, as comparedto levels of Abeta peptide in one or more cells of a correspondingindividual that is not treated with the anti-TREM2 antibody.

In some embodiments, an anti-TREM2 antibody of the present disclosuremay increase memory of an individual by at least 10%, at least 15%, atleast 20%, at least 25%, at least 30%, at least 35%, at least 40%, atleast 45%, at least 50%, at least 55%, at least 60%, at least 65%, atleast 70%, at least 75%, at least 80%, at least 85%, at least 90%, atleast 95%, at least 100%, at least 110%, at least 115%, at least 120%,at least 125%, at least 130%, at least 135%, at least 140%, at least145%, at least 150%, at least 160%, at least 170%, at least 180%, atleast 190%, or at least 200% for example, as compared to the memory of acorresponding individual that is not treated with the anti-TREM2antibody. In other embodiments, an anti-TREM2 antibody of the presentdisclosure increases memory of an individual by at least 1.5 fold, atleast 1.6 fold, at least 1.7 fold, at least 1.8 fold, at least 1.9 fold,at least 2.0 fold, at least 2.1 fold, at least 2.15 fold, at least 2.2fold, at least 2.25 fold, at least 2.3 fold, at least 2.35 fold, atleast 2.4 fold, at least 2.45 fold, at least 2.5 fold, at least 2.55fold, at least 3.0 fold, at least 3.5 fold, at least 4.0 fold, at least4.5 fold, at least 5.0 fold, at least 5.5 fold, at least 6.0 fold, atleast 6.5 fold, at least 7.0 fold, at least 7.5 fold, at least 8.0 fold,at least 8.5 fold, at least 9.0 fold, at least 9.5 fold, or at least 10fold, for example, as compared to the memory of a correspondingindividual that is not treated with the anti-TREM2 antibody.

In some embodiments, an anti-TREM2 antibody of the present disclosuremay reduce cognitive deficit in an individual by at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, at least 45%, at least 50%, at least 55%, at least 60%, at least65%, at least 70%, at least 75%, at least 80%, at least 85%, at least90%, at least 95%, at least 100%, at least 110%, at least 115%, at least120%, at least 125%, at least 130%, at least 135%, at least 140%, atleast 145%, at least 150%, at least 160%, at least 170%, at least 180%,at least 190%, or at least 200% for example, as compared to cognitivedeficit in a corresponding individual that is not treated with theanti-TREM2 antibody. In other embodiments, an anti-TREM2 antibody of thepresent disclosure reduces cognitive deficit an individual by at least1.5 fold, at least 1.6 fold, at least 1.7 fold, at least 1.8 fold, atleast 1.9 fold, at least 2.0 fold, at least 2.1 fold, at least 2.15fold, at least 2.2 fold, at least 2.25 fold, at least 2.3 fold, at least2.35 fold, at least 2.4 fold, at least 2.45 fold, at least 2.5 fold, atleast 2.55 fold, at least 3.0 fold, at least 3.5 fold, at least 4.0fold, at least 4.5 fold, at least 5.0 fold, at least 5.5 fold, at least6.0 fold, at least 6.5 fold, at least 7.0 fold, at least 7.5 fold, atleast 8.0 fold, at least 8.5 fold, at least 9.0 fold, at least 9.5 fold,or at least 10 fold, for example, as compared to cognitive deficit in acorresponding individual that is not treated with the anti-TREM2antibody.

In some embodiments, an anti-TREM2 antibody of the present disclosuremay increase motor coordination in an individual by at least 10%, atleast 15%, at least 20%, at least 25%, at least 30%, at least 35%, atleast 40%, at least 45%, at least 50%, at least 55%, at least 60%, atleast 65%, at least 70%, at least 75%, at least 80%, at least 85%, atleast 90%, at least 95%, at least 100%, at least 110%, at least 115%, atleast 120%, at least 125%, at least 130%, at least 135%, at least 140%,at least 145%, at least 150%, at least 160%, at least 170%, at least180%, at least 190%, or at least 200% for example, as compared to motorcoordination in a corresponding individual that is not treated with theanti-TREM2 antibody. In other embodiments, an anti-TREM2 antibody of thepresent disclosure increases motor coordination an individual by atleast 1.5 fold, at least 1.6 fold, at least 1.7 fold, at least 1.8 fold,at least 1.9 fold, at least 2.0 fold, at least 2.1 fold, at least 2.15fold, at least 2.2 fold, at least 2.25 fold, at least 2.3 fold, at least2.35 fold, at least 2.4 fold, at least 2.45 fold, at least 2.5 fold, atleast 2.55 fold, at least 3.0 fold, at least 3.5 fold, at least 4.0fold, at least 4.5 fold, at least 5.0 fold, at least 5.5 fold, at least6.0 fold, at least 6.5 fold, at least 7.0 fold, at least 7.5 fold, atleast 8.0 fold, at least 8.5 fold, at least 9.0 fold, at least 9.5 fold,or at least 10 fold, for example, as compared to motor coordination in acorresponding individual that is not treated with the anti-TREM2antibody.

Other aspects of the present disclosure relate to methods of enhancingone or more TREM2 activities induced by binding of one or more TREM2ligands to a TREM2 protein in an individual in need thereof, byadministering to the individual a therapeutically effective amount of ananti-TREM2 antibody of the present disclosure. Other aspects of thepresent disclosure relate to methods of inducing one or more TREM2activities in an individual in need thereof, by administering to theindividual a therapeutically effective amount of an anti-TREM2 antibodyof the present disclosure. Any suitable method for measuring TREM2activity, such as the in vitro cell-based assays or in vivo models ofthe present disclosure may be used. Exemplary TREM2 activities include,without limitation, TREM2 binding to DAP12; TREM2 phosphorylation; DAP12phosphorylation; activation of one or more tyrosine kinases, optionallywhere the one or more tyrosine kinases comprise a Syk kinase, ZAP70kinase, or both; activation of phosphatidylinositol 3-kinase (PI3K);activation of protein kinase B (Akt); recruitment of phospholipaseC-gamma (PLC-gamma) to a cellular plasma membrane, activation ofPLC-gamma, or both; recruitment of TEC-family kinase dVav to a cellularplasma membrane; activation of nuclear factor-rB (NF-rB); inhibition ofMAPK signaling; phosphorylation of linker for activation of T cells(LAT), linker for activation of B cells (LAB), or both; activation ofIL-2-induced tyrosine kinase (Itk); transient activation followed byinhibition of one or more pro-inflammatory mediators selected fromIFN-α4, IFN-b, IL-1β, TNF-α, IL-10, IL-6, IL-8, CRP, TGF-beta members ofthe chemokine protein families, IL-20 family members, IL-33, LIF,IFN-gamma, OSM, CNTF, TGF-beta, GM-CSF, IL-11, IL-12, IL-17, IL-18,IL-23, CXCL10, VEGF, CCL4, and MCP-1, optionally where the transientactivation followed by inhibition occur in one or more cells selectedfrom macrophages, M1 macrophages, activated M1 macrophages, M2macrophages, dendritic cells, monocytes, osteoclasts, Langerhans cellsof skin, Kupffer cells, and microglial cells; phosphorylation ofextracellular signal-regulated kinase (ERK); increased expression of C-Cchemokine receptor 7 (CCR7) in one or more cells selected frommacrophages, M1 macrophages, activated M1 macrophages, M2 macrophages,dendritic cells, monocytes, osteoclasts, Langerhans cells of skin,Kupffer cells, microglia, M1 microglia, activated M1 microglia, and M2microglia, and any combination thereof; induction of microglial cellchemotaxis toward CCL19 and CCL21 expressing cells; normalization ofdisrupted TREM2/DAP12-dependent gene expression; recruitment of Syk,ZAP70, or both to a DAP12/TREM2 complex; increasing activity of one ormore TREM2-dependent genes, optionally where the one or moreTREM2-dependent genes comprise nuclear factor of activated T-cells(NFAT) transcription factors; increased maturation of dendritic cells,monocytes, microglia, M1 microglia, activated M1 microglia, and M2microglia, macrophages, M1 macrophages, activated M1 macrophages, M2macrophages, or any combination thereof; increased ability of dendriticcells, monocytes, microglia, M1 microglia, activated M1 microglia, andM2 microglia, macrophages, M1 macrophages, activated M1 macrophages, M2macrophages, or any combination thereof to induce T-cell proliferation;enhanced ability, normalized ability, or both of bone marrow-deriveddendritic cells to induce antigen-specific T-cell proliferation;induction of osteoclast production, increased rate ofosteoclastogenesis, or both; increased survival of dendritic cells,macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages,monocytes, osteoclasts, Langerhans cells of skin, Kupffer cells,microglia, M1 microglia, activated M1 microglia, and M2 microglia, orany combination thereof; increasing the function of dendritic cells,macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages,microglia, M1 microglia, activated M1 microglia, and M2 microglia, orany combination thereof; modulating phagocytosis by dendritic cells,macrophages, M1 macrophages, activated M1 macrophages, M2 macrophages,monocytes, microglia, M1 microglia, activated M1 microglia, and M2microglia, or any combination thereof; induction of one or more types ofclearance selected from apoptotic neuron clearance, nerve tissue debrisclearance, non-nerve tissue debris clearance, bacteria or other foreignbody clearance, disease-causing agent clearance, tumor cell clearance,or any combination thereof, optionally where the disease-causing agentis selected from amyloid beta or fragments thereof, Tau, IAPP,alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin,calcitonin, superoxide dismutase, ataxin, Lewy body, atrial natriureticfactor, islet amyloid polypeptide, insulin, apolipoprotein AI, serumamyloid A, medin, prolactin, transthyretin, lysozyme, beta 2microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin lightchain AL, S-IBM protein, and Repeat-associated non-ATG (RAN) translationproducts including DiPeptide Repeats, (DPRs peptides) composed ofglycine-alanine (GA), glycine-proline (GP), glycine-arginine (GR),proline-alanine (PA), or proline-arginine (PR), antisense GGCCCC (G2C4)repeat-expansion RNA; induction of phagocytosis of one or more ofapoptotic neurons, nerve tissue debris, non-nerve tissue debris,bacteria, other foreign bodies, disease-causing agents, tumor cells, orany combination thereof, optionally where the disease-causing agent isselected from amyloid beta or fragments thereof, Tau, IAPP,alpha-synuclein, TDP-43, FUS protein, prion protein, PrPSc, huntingtin,calcitonin, superoxide dismutase, ataxin, Lewy body, atrial natriureticfactor, islet amyloid polypeptide, insulin, apolipoprotein AI, serumamyloid A, medin, prolactin, transthyretin, lysozyme, beta 2microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin lightchain AL, S-IBM protein, and Repeat-associated non-ATG (RAN) translationproducts including DiPeptide Repeats, (DPRs peptides) composed ofglycine-alanine (GA), glycine-proline (GP), glycine-arginine (GR),proline-alanine (PA), or proline-arginine (PR), antisense GGCCCC (G2C4)repeat-expansion RNA; increased expression of one or more stimulatorymolecules selected from CD83, CD86 MHC class II, CD40, and anycombination thereof, optionally where the CD40 is expressed on dendriticcells, monocytes, macrophages, or any combination thereof, andoptionally where the dendritic cells comprise bone marrow-deriveddendritic cells; reduced secretion of one or more inflammatorymediators, optionally where the one or more inflammatory mediators areselected from CD86, IFN-a4, IFN-b, IL-1β, TNF-α, IL-10, IL-6, IL-8, CRP,TGF-beta members of the chemokine protein families, IL-20 familymembers, IL-33, LIF, IFN-gamma, OSM, CNTF, TGF-beta, GM-CSF, IL-11,IL-12, IL-17, IL-18, IL-23, CXCL10, VEGF, CCL4, and MCP-1, and anycombination thereof; increased memory; and reduced cognitive deficit.

As disclosed herein, anti-TREM2 antibodies of the present disclosure maybe used for decreasing cellular levels of TREM2 on one or more cells,including without limitation, dendritic cells, bone marrow-deriveddendritic cells, monocytes, microglia, macrophages, neutrophils, NKcells, osteoclasts, Langerhans cells of skin, and Kupffer cells and/orcell lines. In some embodiments, the present disclosure provides methodsof decreasing cellular levels of TREM2 on one or more cells in anindividual in need thereof, by administering to the individual atherapeutically effective amount of an anti-TREM2 antibody of thepresent disclosure. In some embodiments, the one or more cells areselected from dendritic cells, bone marrow-derived dendritic cells,monocytes, microglia, macrophages, neutrophils, NK cells, osteoclasts,Langerhans cells of skin, and Kupffer cells, and any combinationthereof. Cellular levels of TREM2 may refer to, without limitation, cellsurface levels of TREM2, intracellular levels of TREM2, and total levelsof TREM2. In some embodiments, a decrease in cellular levels of TREM2comprises decrease in cell surface levels of TREM2. As used herein, cellsurface levels of TREM2 may be measured by any in vitro cell-basedassays or suitable in vivo model described herein or known in the art.In some embodiments, a decrease in cellular levels of TREM2 comprises adecrease in intracellular levels of TREM2. As used herein, intracellularlevels of TREM2 may be measured by any in vitro cell-based assays orsuitable in vivo model described herein or known in the art. In someembodiments, a decrease in cellular levels of TREM2 comprises a decreasein total levels of TREM2. As used herein, total levels of TREM2 may bemeasured by any in vitro cell-based assays or suitable in vivo modeldescribed herein or known in the art. In some embodiments, theanti-TREM2 antibodies induce TREM2 degradation, TREM2 cleavage, TREM2internalization, TREM2 shedding, and/or downregulation of TREM2expression. In some embodiments, cellular levels of TREM2 are measuredon primary cells (e.g., dendritic cells, bone marrow-derived dendriticcells, monocytes, microglia, and macrophages) or on cell lines utilizingan in vitro cell assay.

As disclosed herein, anti-TREM2 antibodies of the present disclosure mayalso be used for increasing memory and/or reducing cognitive deficit. Insome embodiments, the present disclosure provides methods of increasingmemory and/or reducing cognitive deficit in an individual in needthereof, by administering to the individual a therapeutically effectiveamount of an anti-TREM2 antibody of the present disclosure.

In certain embodiments, the individual has a heterozygous TREM2 variantallele having an glutamic acid to stop codon substitution in the nucleicacid sequence encoding amino acid residue 14 of the human TREM2 protein(SEQ ID NO: 1). In certain embodiments, the individual has aheterozygous TREM2 variant allele having a glutamine to stop codonsubstitution in the nucleic acid sequence encoding amino acid residue 33of the human TREM2 protein (SEQ ID NO: 1). In certain embodiments, theindividual has a heterozygous TREM2 variant allele having a tryptophanto stop codon substitution in the nucleic acid sequence encoding aminoacid residue 44 of the human TREM2 protein (SEQ ID NO: 1). In certainembodiments, the individual has a heterozygous TREM2 variant allelehaving an arginine to histidine amino acid substitution at amino acidresidue 47 of the human TREM2 protein (SEQ ID NO: 1). In certainembodiments, the individual has a heterozygous TREM2 variant allelehaving a tryptophan to stop codon substitution in the nucleic acidsequence encoding amino acid residue 78 of the human TREM2 protein (SEQID NO: 1). In certain embodiments, the individual has a heterozygousTREM2 variant allele having a valine to glycine amino acid substitutionat an amino acid corresponding to amino acid residue 126 of the humanTREM2 protein (SEQ ID NO: 1). In certain embodiments, the individual hasa heterozygous TREM2 variant allele having an aspartic acid to glycineamino acid substitution at an amino acid corresponding to amino acidresidue 134 of the human TREM2 protein (SEQ ID NO: 1). In certainembodiments, the individual has a heterozygous TREM2 variant allelehaving a lysine to asparagine amino acid substitution at an amino acidcorresponding to amino acid residue 186 of the human TREM2 protein (SEQID NO: 1).

In some embodiments, the individual has a heterozygous TREM2 variantallele having a guanine nucleotide deletion at a nucleotidecorresponding to nucleotide residue G313 of the nucleic acid sequenceencoding SEQ ID NO: 1; a guanine nucleotide deletion at a nucleotidecorresponding to nucleotide residue G267 of the nucleic acid sequenceencoding SEQ ID NO: 1; a threonine to methionine amino acid substitutionat an amino acid corresponding to amino acid residue Thr66 of SEQ ID NO:1; and/or a serine to cysteine amino acid substitution at an amino acidcorresponding to amino acid residue Ser 16 of SEQ ID NO: 1.

As disclosed herein, anti-TREM2 antibodies of the present disclosure mayalso be used for inducing and/or promoting innate immune cell survival.In some embodiments, the present disclosure provides methods of inducingor promoting innate immune cell survival in an individual in needthereof, by administering to the individual a therapeutically effectiveamount of an anti-TREM2 antibody of the present disclosure.

As disclosed herein, anti-TREM2 antibodies of the present disclosure mayalso be used for inducing and/or promoting wound healing, such as afterinjury. In some embodiments, the wound healing may be colonic woundrepair following injury. In some embodiments, the present disclosureprovides methods of inducing or promoting wound healing an individual inneed thereof, by administering to the individual a therapeuticallyeffective amount of an anti-TREM2 antibody of the present disclosure.

In some embodiments, the methods of the present disclosure may involvethe coadministration of anti-TREM2 antibodies, or bispecific antibodieswith TLR antagonists or with agents neutralizing TLR agonist (e.g.,neutralizing cytokine or interleukin antibodies).

In some embodiments, the methods of the present disclosure may involvethe administration of chimeric constructs, including an anti-TREM2antibody of the present disclosure in conjunction with a TREM2 ligand,such as HSP60.

In some embodiments, the anti-TREM2 antibodies of the present disclosuredo not inhibit the growth of one or more innate immune cells. In someembodiments, the anti-TREM2 antibodies of the present disclosure bind toone or more primary immune cells with a K_(D) of less than 50 nM, lessthan 45 nM, less than 40 nM, less than 35 nM, less than 30 nM, less than25 nM, less than 20 nM, less than 15 nM, less than 10 nM, less than 9nM, less than 8 nM, less than 7 nM, less than 6 nM, less than 5 nM, lessthan 4 nM, less than 3 nM, less than 2 nM, or less than 1 nM. In someembodiments, an anti-TREM2 antibody of the present disclosureaccumulates in the brain, or the cerebrospinal fluid (CSF), or both toan extent that is 1% or more, 2% or more, 3% or more, 4% or more, 5% ormore, 6% or more, 7% or more, 8% or more, 9% or more, 10% or more of theconcentration of the antibody in the blood.

In some embodiments, a subject or individual is a mammal. Mammalsinclude, without limitation, domesticated animals (e.g., cows, sheep,cats, dogs, and horses), primates (e.g., humans and non-human primatessuch as monkeys), rabbits, and rodents (e.g., mice and rats). In someembodiments, the subject or individual is a human.

Dementia

Dementia is a non-specific syndrome (i.e., a set of signs and symptoms)that presents as a serious loss of global cognitive ability in apreviously unimpaired person, beyond what might be expected from normalageing. Dementia may be static as the result of a unique global braininjury. Alternatively, dementia may be progressive, resulting inlong-term decline due to damage or disease in the body. While dementiais much more common in the geriatric population, it can also occurbefore the age of 65. Cognitive areas affected by dementia include,without limitation, memory, attention span, language, and problemsolving. Generally, symptoms must be present for at least six months tobefore an individual is diagnosed with dementia.

Exemplary forms of dementia include, without limitation, frontotemporaldementia, Alzheimer's disease, vascular dementia, semantic dementia, anddementia with Lewy bodies.

In some embodiments, administering an anti-TREM2 antibody of the presentdisclosure can prevent, reduce the risk, and/or treat dementia. In someembodiments, administering an anti-TREM2 antibody may induce one or moreTREM2 activities in an individual having dementia (e.g., DAP12phosphorylation, PI3K activation, increased expression of one or moreanti-inflammatory mediators, or reduced expression of one or morepro-inflammatory mediators).

Frontotemporal Dementia

Frontotemporal dementia (FTD) is a condition resulting from theprogressive deterioration of the frontal lobe of the brain. Over time,the degeneration may advance to the temporal lobe. Second only toAlzheimer's disease (AD) in prevalence, FTD accounts for 20% ofpre-senile dementia cases. The clinical features of FTD include memorydeficits, behavioral abnormalities, personality changes, and languageimpairments (Cruts, M. & Van Broeckhoven, C., Trends Genet. 24:186-194(2008); Neary, D., et al., Neurology 51:1546-1554 (1998); Ratnavalli,E., Brayne, C., Dawson, K. & Hodges, J. R., Neurology 58:1615-1621(2002)).

A substantial portion of FTD cases are inherited in an autosomaldominant fashion, but even in one family, symptoms can span a spectrumfrom FTD with behavioral disturbances, to Primary Progressive Aphasia,to Cortico-Basal Ganglionic Degeneration. FTD, like mostneurodegenerative diseases, can be characterized by the pathologicalpresence of specific protein aggregates in the diseased brain.Historically, the first descriptions of FTD recognized the presence ofintraneuronal accumulations of hyperphosphorylated Tau protein inneurofibrillary tangles or Pick bodies. A causal role for themicrotubule associated protein Tau was supported by the identificationof mutations in the gene encoding the Tau protein in several families(Hutton, M., et al., Nature 393:702-705 (1998). However, the majority ofFTD brains show no accumulation of hyperphosphorylated Tau but doexhibit immunoreactivity to ubiquitin (Ub) and TAR DNA binding protein(TDP43) (Neumann, M., et al., Arch. Neurol. 64:1388-1394 (2007)). Amajority of those FTD cases with Ub inclusions (FTD-U) were shown tocarry mutations in the progranulin gene.

In some embodiments, administering an anti-TREM2 antibody of the presentdisclosure can prevent, reduce the risk, and/or treat FTD. In someembodiments, administering an anti-TREM2 antibody may induce one or moreTREM2 activities in an individual having FTD (e.g., DAP12phosphorylation, PI3K activation, increased expression of one or moreanti-inflammatory mediators, or reduced expression of one or morepro-inflammatory mediators).

Alzheimer's Disease

Alzheimer's disease (AD) is the most common form of dementia. There isno cure for the disease, which worsens as it progresses, and eventuallyleads to death. Most often, AD is diagnosed in people over 65 years ofage. However, the less-prevalent early-onset Alzheimer's can occur muchearlier.

Common symptoms of Alzheimer's disease include, behavioral symptoms,such as difficulty in remembering recent events; cognitive symptoms,confusion, irritability and aggression, mood swings, trouble withlanguage, and long-term memory loss. As the disease progresses bodilyfunctions are lost, ultimately leading to death. Alzheimer's diseasedevelops for an unknown and variable amount of time before becomingfully apparent, and it can progress undiagnosed for years.

In some embodiments, administering an anti-TREM2 antibody of the presentdisclosure can prevent, reduce the risk, and/or treat Alzheimer'sdisease. In some embodiments, administering an anti-TREM2 antibody mayinduce one or more TREM2 activities in an individual having Alzheimer'sdisease (e.g., DAP12 phosphorylation, PI3K activation, increasedexpression of one or more anti-inflammatory mediators, or reducedexpression of one or more pro-inflammatory mediators).

Nasu-Hakola Disease

Nasu-Hakola disease (NHD), which may alternatively be referred to aspolycystic lipomembranous osteodysplasia with sclerosingleukoencephalopathy (PLOSL), is a rare inherited leukodystrophycharacterized by progressive presenile dementia associated withrecurrent bone fractures due to polycystic osseous lesions of the lowerand upper extremities. NHD disease course is generally divided into fourstages: latent, osseous, early neurologic, and late neurologic. After anormal development during childhood (latent stage), NHD startsmanifesting during adolescence or young adulthood (typical age of onset20-30 years) with pain in the hands, wrists, ankles, and feet. Patientsthen start suffering from recurrent bone fractures due to polycysticosseous and osteroporotic lesions in the limb bones (osseous stage).During the third or fourth decade of life (early neurologic stage),patients present with pronounced personality changes (e.g., euphoria,lack of concentration, loss of judgment, and social inhibitions)characteristic of a frontal lobe syndrome. Patients also typicallysuffer from progressive memory disturbances. Epileptic seizures are alsofrequently observed. Finally (late neurologic stage), patients progressto a profound dementia, are unable to speak and move, and usually die bythe age of 50.

In some embodiments, administering an anti-TREM2 antibody of the presentdisclosure can prevent, reduce the risk, and/or treat Nasu-Hakoladisease (NHD). In some embodiments, administering an anti-TREM2 antibodymay induce one or more TREM2 activities in an individual having NHD(e.g., DAP12 phosphorylation, PI3K activation, increased expression ofone or more anti-inflammatory mediators, or reduced expression of one ormore pro-inflammatory mediators).

Parkinson's Disease

Parkinson's disease, which may be referred to as idiopathic or primaryparkinsonism, hypokinetic rigid syndrome (HRS), or paralysis agitans, isa neurodegenerative brain disorder that affects motor system control.The progressive death of dopamine-producing cells in the brain leads tothe major symptoms of Parkinson's. Most often, Parkinson's disease isdiagnosed in people over 50 years of age. Parkinson's disease isidiopathic (having no known cause) in most people. However, geneticfactors also play a role in the disease.

Symptoms of Parkinson's disease include, without limitation, tremors ofthe hands, arms, legs, jaw, and face, muscle rigidity in the limbs andtrunk, slowness of movement (bradykinesia), postural instability,difficulty walking, neuropsychiatric problems, changes in speech orbehavior, depression, anxiety, pain, psychosis, dementia,hallucinations, and sleep problems.

In some embodiments, administering an anti-TREM2 antibody of the presentdisclosure can prevent, reduce the risk, and/or treat Parkinson'sdisease. In some embodiments, administering an anti-TREM2 antibody mayinduce one or more TREM2 activities in an individual having Parkinson'sdisease (e.g., DAP12 phosphorylation, PI3K activation, increasedexpression of one or more anti-inflammatory mediators, or reducedexpression of one or more pro-inflammatory mediators).

Amyotrophic Lateral Sclerosis

As used herein, amyotrophic lateral sclerosis (ALS) or, motor neurondisease or, Lou Gehrig's disease are used interchangeably and refer to adebilitating disease with varied etiology characterized by rapidlyprogressive weakness, muscle atrophy and fasciculations, musclespasticity, difficulty speaking (dysarthria), difficulty swallowing(dysphagia), and difficulty breathing (dyspnea).

It has been shown that progranulin play a role in ALS (Schymick, J C etal., (2007) J Neurol Neurosurg Psychiatry; 78:754-6) and protects againthe damage caused by ALS causing proteins such as TDP-43 (Laird, A S etal., (2010). PLoS ONE 5: e13368). It was also demonstrated that pro-NGFinduces p75 mediated death of oligodendrocytes and corticospinal neuronsfollowing spinal cord injury (Beatty et al., Neuron (2002), 36, pp.375-386; Giehl et al, Proc. Natl. Acad. Sci USA (2004), 101, pp6226-30).

In some embodiments, administering an anti-TREM2 antibody of the presentdisclosure can prevent, reduce the risk, and/or treat ALS. In someembodiments, administering an anti-TREM2 antibody may induce one or moreTREM2 activities in an individual having ALS (e.g., DAP12phosphorylation, PI3K activation, increased expression of one or moreanti-inflammatory mediators, or reduced expression of one or morepro-inflammatory mediators).

Huntington's Disease

Huntington's disease (HD) is an inherited neurodegenerative diseasecaused by an autosomal dominant mutation in the Huntingtin gene (HTT).Expansion of a cytokine-adenine-guanine (CAG) triplet repeat within theHuntingtin gene results in production of a mutant form of the Huntingtinprotein (Htt) encoded by the gene. This mutant Huntingtin protein (mHtt)is toxic and contributes to neuronal death. Symptoms of Huntington'sdisease most commonly appear between the ages of 35 and 44, althoughthey can appear at any age.

Symptoms of Huntington's disease, include, without limitation, motorcontrol problems, jerky, random movements (chorea), abnormal eyemovements, impaired balance, seizures, difficulty chewing, difficultyswallowing, cognitive problems, altered speech, memory deficits,thinking difficulties, insomnia, fatigue, dementia, changes inpersonality, depression, anxiety, and compulsive behavior.

In some embodiments, administering an anti-TREM2 antibody of the presentdisclosure can prevent, reduce the risk, and/or treat Huntington'sdisease (HD). In some embodiments, administering an anti-TREM2 antibodymay induce one or more TREM2 activities in an individual having HD(e.g., DAP12 phosphorylation, PI3K activation, increased expression ofone or more anti-inflammatory mediators, or reduced expression of one ormore pro-inflammatory mediators).

Tauopathy Disease

Tauopathy diseases, or Tauopathies, are a class of neurodegenerativedisease caused by aggregation of the microtubule-associated protein tauwithin the brain. Alzheimer's disease (AD) is the most well-knowntauopathy disease, and involves an accumulation of tau protein withinneurons in the form of insoluble neurofibrillary tangles (NFTs). Othertauopathy diseases and disorders include progressive supranuclear palsy,dementia pugilistica (chromic traumatic encephalopathy), Frontotemporaldementia and parkinsonism linked to chromosome 17, Lytico-Bodig disease(Parkinson-dementia complex of Guam), Tangle-predominant dementia,Ganglioglioma and gangliocytoma, Meningioangiomatosis, Subacutesclerosing panencephalitis, lead encephalopathy, tuberous sclerosis,Hallervorden-Spatz disease, lipofuscinosis, Pick's disease, corticobasaldegeneration, Argyrophilic grain disease (AGD), Huntington's disease,frontotemporal dementia, and frontotemporal lobar degeneration.

In some embodiments, administering an anti-TREM2 antibody of the presentdisclosure can prevent, reduce the risk, and/or treat tauopathy disease.In some embodiments, administering an anti-TREM2 antibody may induce oneor more TREM2 activities in an individual having tauopathy disease(e.g., DAP12 phosphorylation, PI3K activation, increased expression ofone or more anti-inflammatory mediators, or reduced expression of one ormore pro-inflammatory mediators).

Multiple Sclerosis

Multiple sclerosis (MS) can also be referred to as disseminatedsclerosis or encephalomyelitis disseminata. MS is an inflammatorydisease in which the fatty myelin sheaths around the axons of the brainand spinal cord are damaged, leading to demyelination and scarring aswell as a broad spectrum of signs and symptoms. MS affects the abilityof nerve cells in the brain and spinal cord to communicate with eachother effectively. Nerve cells communicate by sending electrical signalscalled action potentials down long fibers called axons, which arecontained within an insulating substance called myelin. In MS, thebody's own immune system attacks and damages the myelin. When myelin islost, the axons can no longer effectively conduct signals. MS onsetusually occurs in young adults, and is more common in women.

Symptoms of MS include, without limitation, changes in sensation, suchas loss of sensitivity or tingling; pricking or numbness, such ashypoesthesia and paresthesia; muscle weakness; clonus; muscle spasms;difficulty in moving; difficulties with coordination and balance, suchas ataxia; problems in speech, such as dysarthria, or in swallowing,such as dysphagia; visual problems, such as nystagmus, optic neuritisincluding phosphenes, and diplopia; fatigue; acute or chronic pain; andbladder and bowel difficulties; cognitive impairment of varying degrees;emotional symptoms of depression or unstable mood; Uhthoffs phenomenon,which is an exacerbation of extant symptoms due to an exposure to higherthan usual ambient temperatures; and Lhermitte's sign, which is anelectrical sensation that runs down the back when bending the neck.

In some embodiments, administering an anti-TREM2 antibody of the presentdisclosure can prevent, reduce the risk, and/or treat multiplesclerosis. In some embodiments, administering an anti-TREM2 antibody mayinduce one or more TREM2 activities in an individual having multiplesclerosis (e.g., DAP12 phosphorylation, PI3K activation, increasedexpression of one or more anti-inflammatory mediators, and reducedexpression of one or more pro-inflammatory mediators).

Cancer

Yet further aspects of the present disclosure provide methods forpreventing, reducing risk, or treating an individual having cancer,comprising administering to the individual a therapeutically effectiveamount of an isolated anti-TREM2 antibody of the present disclosure. Anyof the isolated antibodies of the present disclosure may be used inthese methods.

As described above, the tumor microenvironment is known to contain aheterogeneous immune infiltrate, which includes T lymphocytes,macrophages and cells of myeloid/granulocytic lineage. In particular,the presence of M2-macrophages in tumors is associated with poorprognosis. Therapies that reduce the number of these cells in the tumor,such as CSF-1R blocking agents, are showing beneficial effects inpreclinical models and early stage clinical studies. It has been shownthat TREM2 synergizes with CSF-1 to promote survival of macrophages invitro, and that this effect is particularly prominent in M2-typemacrophages, compared to other types of phagocytic cells. A seminalpreclinical study has also shown synergies between drugs that targettumor-associated macrophages (e.g., CSF-1/CSF-1R blocking antibodies)and checkpoint blocking antibodies that target T cells, indicating thatmanipulating both cell types shows efficacy in tumor models whereindividual therapies are poorly effective (Zhu Y; Cancer Res. 2014 Sep.15; 74(18):5057-69). Therefore, without wishing to be bound by theory,it is thought that blocking TREM2 signaling in tumor associatedmacrophages may inhibit suppression of the immune response in the tumormicroenvironment, resulting in a therapeutic anti-tumor immune response.

Due to the synergies between TREM2 and CSF-1, and between targetingtumor-associated macrophages and targeting T cells, in some embodiments,the methods for preventing, reducing risk, or treating an individualhaving cancer further include administering to the individual at leastone antibody that specifically binds to an inhibitory checkpointmolecule. Examples of antibodies that specifically bind to an inhibitorycheckpoint molecule include, without limitation, an anti-PD-L1 antibody,an anti-CTLA-4 antibody, an anti-PD-L2 antibody, an anti-PD-1 antibody,an anti-B7-H3 antibody, an anti-B7-H4 antibody, and anti-HVEM antibody,an anti-BTLA antibody, an anti-GAL9 antibody, an anti-TIM3 antibody, ananti-A2AR antibody, an anti-LAG-3 antibody, an anti-phosphatidylserineantibody, and any combination thereof. In some embodiments, the at leastone antibody that specifically binds to an inhibitory checkpointmolecule is administered in combination with an anti-TREM2 antibody ofthe present disclosure.

In some embodiments, a cancer to be prevented or treated by the methodsof the present disclosure includes, but is not limited to, squamous cellcancer (e.g., epithelial squamous cell cancer), lung cancer includingsmall-cell lung cancer, non-small cell lung cancer, adenocarcinoma ofthe lung and squamous carcinoma of the lung, cancer of the peritoneum,hepatocellular cancer, gastric or stomach cancer includinggastrointestinal cancer and gastrointestinal stromal cancer, pancreaticcancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer,bladder cancer, cancer of the urinary tract, hepatoma, breast cancer,colon cancer, rectal cancer, colorectal cancer, endometrial or uterinecarcinoma, salivary gland carcinoma, kidney or renal cancer, prostatecancer, vulval cancer, thyroid cancer, hepatic carcinoma, analcarcinoma, penile carcinoma, melanoma, superficial spreading melanoma,lentigo maligna melanoma, acral lentiginous melanomas, nodularmelanomas, multiple myeloma and B-cell lymphoma; chronic lymphocyticleukemia (CLL); acute lymphoblastic leukemia (ALL); hairy cell leukemia;chronic myeloblastic leukemia; and post-transplant lymphoproliferativedisorder (PTLD), as well as abnormal vascular proliferation associatedwith phakomatoses, edema (such as that associated with brain tumors),Meigs' syndrome, brain, as well as head and neck cancer, and associatedmetastases. In some embodiments, the cancer is colorectal cancer. Insome embodiments, the cancer is selected from non-small cell lungcancer, glioblastoma, neuroblastoma, renal cell carcinoma, bladdercancer, ovarian cancer, melanoma, breast carcinoma, gastric cancer, andhepatocellular carcinoma. In some embodiments, the cancer istriple-negative breast carcinoma. In some embodiments, the cancer may bean early stage cancer or a late stage cancer. In some embodiments, thecancer may be a primary tumor. In some embodiments, the cancer may be ametastatic tumor at a second site derived from any of the above types ofcancer.

In some embodiments, anti-TREM2 antibodies of the present disclosure maybe used for preventing, reducing risk, or treating cancer, including,without limitation, bladder cancer breast cancer, colon and rectalcancer, endometrial cancer, kidney cancer, renal cell cancer, renalpelvis cancer, leukemia, lung cancer, melanoma, non-Hodgkin's lymphoma,pancreatic cancer, prostate cancer, ovarian cancer, fibrosarcoma, andthyroid cancer.

In some embodiments, the present disclosure provides methods ofpreventing, reducing risk, or treating an individual having cancer, byadministering to the individual a therapeutically effective amount of ananti-TREM2 antibody of the present disclosure.

In some embodiments, the method further includes administering to theindividual at least one antibody that specifically binds to aninhibitory checkpoint molecule, and/or another standard orinvestigational anti-cancer therapy. In some embodiments, the at leastone antibody that specifically binds to an inhibitory checkpointmolecule is administered in combination with the isolated antibody. Insome embodiments, the at least one antibody that specifically binds toan inhibitory checkpoint molecule is selected from an anti-PD-L1antibody, an anti-CTLA-4 antibody, an anti-PD-L2 antibody, an anti-PD-1antibody, an anti-B7-H3 antibody, an anti-B7-H4 antibody, and anti-HVEMantibody, an anti-B- and T-lymphocyte attenuator (BTLA) antibody, ananti-Killer inhibitory receptor (KIR) antibody, an anti-GAL9 antibody,an anti-TIM3 antibody, an anti-A2AR antibody, an anti-LAG-3 antibody, ananti-phosphatidylserine antibody, an anti-CD27 antibody, and anycombination thereof. In some embodiments, the standard orinvestigational anti-cancer therapy is one or more therapies selectedfrom radiotherapy, cytotoxic chemotherapy, targeted therapy, imatinib(Gleevec®), trastuzumab (Herceptin®), adoptive cell transfer (ACT),chimeric antigen receptor T cell transfer (CAR-T), vaccine therapy,hormonal therapy, bevacizumab (Avastin®), Ofatumumab (Arzerra®),Rituximab (Rituxan®, MabThera®, Zytux®), cryotherapy, ablation,radiofrequency ablation, and cytokine therapy.

In some embodiments, the method further includes administering to theindividual at least one antibody that specifically binds to aninhibitory cytokine. In some embodiments, the at least one antibody thatspecifically binds to an inhibitory cytokine is administered incombination with the isolated antibody. In some embodiments, the atleast one antibody that specifically binds to an inhibitory cytokine isselected from an anti-CCL2 antibody, an anti-CSF-1 antibody, ananti-IL-2 antibody, and any combination thereof.

In some embodiments, the method further includes administering to theindividual at least one agonistic antibody that specifically binds to astimulatory checkpoint protein. In some embodiments, the at least oneagonistic antibody that specifically binds to a stimulatory checkpointprotein is administered in combination with the isolated antibody. Insome embodiments, the at least one agonistic antibody that specificallybinds to a stimulatory checkpoint protein is selected from an agonistanti-CD40 antibody, an agonist anti-OX40 antibody, an agonist anti-ICOSantibody, an agonist anti-CD28 antibody, an agonist anti-CD137/4-1BBantibody, an agonist anti-CD27 antibody, an agonistanti-glucocorticoid-induced TNFR-related protein GITR antibody, and anycombination thereof.

In some embodiments, the method further includes administering to theindividual at least one stimulatory cytokine. In some embodiments, theat least one stimulatory cytokine is administered in combination withthe isolated antibody. In some embodiments, the at least one stimulatorycytokine is selected from TNF-α, IL-1□, IL-1β, IL-10, IL-6, IL-8, CRP,TGF-beta members of the chemokine protein families, IL-20 familymembers, IL-33, LIF, IFN-gamma, OSM, CNTF, TGF-beta, IL-11, IL-12,IL-17, IL-8, CRP, IFN-α, IFN-β, IL-2, IL-18, IL-23, CXCL10, CCL4, MCP-1,VEGF, GM-CSF, G-CSF, and any combination thereof.

Kits/Articles of Manufacture

The present disclosure also provides kits containing an isolatedantibody of the present disclosure (e.g., an anti-TREM2 antibodydescribed herein), or a functional fragment thereof. Kits of the presentdisclosure may include one or more containers comprising a purifiedantibody of the present disclosure. In some embodiments, the kitsfurther include instructions for use in accordance with the methods ofthis disclosure. In some embodiments, these instructions comprise adescription of administration of the isolated antibody of the presentdisclosure (e.g., an anti-TREM2 antibody described herein) to prevent,reduce risk, or treat an individual having a disease, disorder, orinjury selected from dementia, frontotemporal dementia, Alzheimer'sdisease, Nasu-Hakola disease, multiple sclerosis, and cancer, accordingto any methods of this disclosure.

In some embodiments, the instructions comprise a description of how todetect TREM2, for example in an individual, in a tissue sample, or in acell. The kit may further comprise a description of selecting anindividual suitable for treatment based on identifying whether thatindividual has the disease and the stage of the disease.

In some embodiments, the kits may further include another antibody ofthe present disclosure (e.g., at least one antibody that specificallybinds to an inhibitory checkpoint molecule, at least one antibody thatspecifically binds to an inhibitory cytokine, and/or at least oneagonistic antibody that specifically binds to a stimulatory checkpointprotein) and/or at least one stimulatory cytokine. In some embodiments,the kits may further include instructions for using the antibody and/orstimulatory cytokine in combination with an isolated antibody of thepresent disclosure (e.g., an anti-TREM2 antibody described herein),instructions for using the isolated antibody of the present disclosurein combination with an antibody and/or stimulatory cytokine, orinstructions for using an isolated antibody of the present disclosureand an antibody and/or stimulatory cytokine, according to any methods ofthis disclosure.

The instructions generally include information as to dosage, dosingschedule, and route of administration for the intended treatment. Thecontainers may be unit doses, bulk packages (e.g., multi-dose packages)or sub-unit doses. Instructions supplied in the kits of the presentdisclosure are typically written instructions on a label or packageinsert (e.g., a paper sheet included in the kit), but machine-readableinstructions (e.g., instructions carried on a magnetic or opticalstorage disk) are also acceptable.

The label or package insert indicates that the composition is used fortreating, e.g., a disease of the present disclosure. Instructions may beprovided for practicing any of the methods described herein.

The kits of this disclosure are in suitable packaging. Suitablepackaging includes, but is not limited to, vials, bottles, jars,flexible packaging (e.g., sealed Mylar or plastic bags), and the like.Also contemplated are packages for use in combination with a specificdevice, such as an inhaler, nasal administration device (e.g., anatomizer) or an infusion device such as a minipump. A kit may have asterile access port (for example the container may be an intravenoussolution bag or a vial having a stopper pierceable by a hypodermicinjection needle). The container may also have a sterile access port(e.g., the container may be an intravenous solution bag or a vial havinga stopper pierceable by a hypodermic injection needle). At least oneactive agent in the composition is an isolated antibody of the presentdisclosure (e.g., an anti-TREM2 antibody described herein). Thecontainer may further comprise a second pharmaceutically active agent.

Kits may optionally provide additional components such as buffers andinterpretive information. Normally, the kit comprises a container and alabel or package insert(s) on or associated with the container.

Diagnostic Uses

The isolated antibodies of the present disclosure (e.g., an anti-TREM2antibody described herein) also have diagnostic utility. This disclosuretherefore provides for methods of using the antibodies of thisdisclosure, or functional fragments thereof, for diagnostic purposes,such as the detection of TREM2 in an individual or in tissue samplesderived from an individual.

In some embodiments, the individual is a human. In some embodiments, theindividual is a human patient suffering from, or at risk for developing,cancer. In some embodiments, the diagnostic methods involve detectingTREM2 in a biological sample, such as a biopsy specimen, a tissue, or acell. An isolated antibody of the present disclosure (e.g., ananti-TREM2 antibody described herein) is contacted with the biologicalsample and antigen-bound antibody is detected. For example, a tumorsample (e.g., a biopsy specimen) may be stained with an anti-TREM2antibody described herein in order to detect and/or quantifytumor-associated macrophages (e.g., M2-type macrophages). The detectionmethod may involve quantification of the antigen-bound antibody.Antibody detection in biological samples may occur with any method knownin the art, including immunofluorescence microscopy,immunocytochemistry, immunohistochemistry, ELISA, FACS analysis,immunoprecipitation, or micro-positron emission tomography. In certainembodiments, the antibody is radiolabeled, for example with ¹⁸F andsubsequently detected utilizing micro-positron emission tomographyanalysis. Antibody-binding may also be quantified in a patient bynon-invasive techniques such as positron emission tomography (PET),X-ray computed tomography, single-photon emission computed tomography(SPECT), computed tomography (CT), and computed axial tomography (CAT).

In other embodiments, an isolated antibody of the present disclosure(e.g., an anti-TREM2 antibody described herein) may be used to detectand/or quantify, for example, microglia in a brain specimen taken from apreclinical disease model (e.g., a non-human disease model). As such, anisolated antibody of the present disclosure (e.g., an anti-TREM2antibody described herein) may be useful in evaluating therapeuticresponse after treatment in a model for a nervous system disease orinjury such as dementia, frontotemporal dementia, Alzheimer's disease,Nasu-Hakola disease, or multiple sclerosis, as compared to a control.

Antibodies with Modified Constant Regions

Other aspects of the present disclosure relate to antibodies havingmodified constant regions (i.e., Fc regions). In some embodiments themodified Fc regions include two or more amino acid substitutions thatincrease antibody clustering without activating complement as comparedto a corresponding antibody having an Fc region that does not includethe two or more amino acid substitutions. Accordingly, in someembodiments, the antibody is an antibody comprising an Fc region, wherethe antibody comprises an amino acid substitution at position E430G andone or more amino acid substitutions in the Fc region at a residueposition selected from: L234F, L235A, L235E, S267E, K322A, L328F, A330S,P331S, and any combination thereof, where the numbering of the residuesis according to EU or Kabat numbering. In some embodiments, the Fcregion comprises an amino acid substitution at positions E430G, L243A,L235A, and P331S, where the numbering of the residue position isaccording to EU numbering. In some embodiments, the Fc region comprisesan amino acid substitution at positions E430G and P331S, where thenumbering of the residue position is according to EU numbering. In someembodiments, the Fc region comprises an amino acid substitution atpositions E430G and K322A, where the numbering of the residue positionis according to EU numbering. In some embodiments, the Fc regioncomprises an amino acid substitution at positions E430G, A330S, andP331S, where the numbering of the residue position is according to EUnumbering. In some embodiments, the Fc region comprises an amino acidsubstitution at positions E430G, K322A, A330S, and P331S, where thenumbering of the residue position is according to EU numbering. In someembodiments, the Fc region comprises an amino acid substitution atpositions E430G, K322A, and A330S, where the numbering of the residueposition is according to EU numbering. In some embodiments, the Fcregion comprises an amino acid substitution at positions E430G, K322A,and P331S, where the numbering of the residue position is according toEU numbering.

In some embodiments, the Fc region increases clustering withoutactivating complement as compared to a corresponding antibody comprisingan Fc region that does not comprise the amino acid substitutions. Insome embodiments, the antibody induces one or more activities of atarget specifically bound by the antibody. In some embodiments, theantibody binds to TREM2.

The present disclosure will be more fully understood by reference to thefollowing Examples. They should not, however, be construed as limitingthe scope of the present disclosure. All citations throughout thedisclosure are hereby expressly incorporated by reference.

EXAMPLES Example 1: Humanized AL2p Antibodies Retain Affinity andFunction

The mouse anti-TREM2 antibody AL2p is also known as 9F5 and 9F5a in WO2017/062672 (PCT/US2016/055828).

Methods

Humanized versions of the mouse anti-TREM2 antibody AL2p were generatedby combining 21 human IgG1 versions of VH with 6 human IgG1 versions ofVK, each containing from 0 to 11 framework residue mutations. Thesevariants were tested by ForteBio for affinity to the TREM2 antigen and94 variants were chosen for further in vitro analysis.

The affinity of the TREM2 antibodies was determined by measuring theirK_(D), as well as on- and off-rates by ForteBio OctetRed as previouslydescribed by Estep et al., Mabs 2013: 5(2):270-278. Briefly, IgG's wereloaded on-line onto AHQ sensors. Sensors were equilibrated off-line inassay buffer for 30 minutes and then monitored on-line for 60 secondsfor baseline establishment. For avid binding measurement, sensors withloaded IgGs were exposed to 100 nM antigen (human TREM2 Fc fusion usingthe entire TREM2 ECD; only one Fc arm was fused to TREM2) for 3 minutes,afterwards they were transferred to assay buffer for 3 minutes foroff-rate measurement. Monovalent binding measurements were obtained byloading human TREM2 Fc fusion antigens to AHQ sensor and followed byexposure to −100 nM TREM2 antibody Fab. Kinetics data were fit using a1:1 binding model in the data analysis software provided by ForteBio.Assay was run at room temperature (25° C.).

To examine cell binding of anti-TREM2 antibodies, recombinant, humanTREM2-expressing BW5147.G.1.4 cells (ATCC® TIB48™) were established bystably expressing either mouse TREM2 or human TREM2 together with Dap12using viral infection. Cells were harvested by scraping, washed in PBS,counted and plated on 96-well U bottom plates at 1×10⁵ cells/well. Theplates were spun at 1,400 rpm for 3 minutes and primary anti-TREM2 orcontrol antibodies were added in FACS buffer (PBS+2% FBS) and incubatedon ice for one hour. Cells were subsequently centrifuged as before andwashed thrice with FACS buffer. Cells were then incubated withanti-human PE conjugated secondary antibody (BD Biosciences) in FACSbuffer for 30 minutes on ice. Cells were again washed thrice with FACSbuffer and analyzed on a BD FACS Canto. Binding was measured as meanfluorescence intensity in the APC channel.

The ability of plate-bound full-length anti-TREM2 antibodies to activatehuman TREM2-dependent genes was evaluated using a luciferase reportergene under the control of an NFAT (nuclear factor of activated T-cells)promoter. The cell line BW5147.G.1.4, derived from mouse thymus lymphomaT lymphocytes, was infected with a human TREM2/DAP12 fusion protein, andwith Cignal Lenti NFAT-Luciferase virus (Qiagen). To test antibodies insolution, they were added to the culture plates together with the cellsand incubated for 4 to 6 hours at 37° C. Luciferase activity wasmeasured by adding OneGlo Reagent (Promega) to each well and incubatingfor 3 minutes at room temperature on a plate shaker. Luciferase signalwas measured using a BioTek plate reader.

Results

Humanized versions of anti-TREM2 antibody AL2p were generated bycombining 21 human IgG1 versions of VH with 6 human IgG1 versions of VK,each containing from 0 to 11 framework residue mutations. The heavychain and light chain variable region sequences of 26 humanizedanti-TREM2 antibodies are depicted in Tables 6 and 7.

Clones were tested for affinity to human TREM2 by ForteBio Octet Red(Table 1). Most humanized AL2p variants retained a similar affinity asthe human mouse AL2p chimeric parental antibody (which has a mouseantibody variable region and a human Fc region). In addition, humanizedvariants retained ability to bind to human TREM2 expressed on BW cells,with some even showing an improved affinity over the parental antibody(Table 1). Furthermore, humanized variants retained the ability toinduce TREM2 signaling in a heterologous NFAT:luciferase signaling assay(Table 1). Two variants (AL2p-h50 and AL2p-h77) were chosen to move intoaffinity maturation as they both retained affinity and function of theparental antibody, while containing few changes from human germlineindicating low immunogenicity.

TABLE 1 Characterization of humanized versions of anti-TREM2 antibodyAL2p Soluble luciferase Fab K_(D) human Cell binding human activation atTREM2-Fc (M) TREM2/DAP12 10 μg/ml Fold Antibody Monovalent BWZ (FOB)over control AL2p 1.02E−07 79 3.55 AL2p-h19 1.93E−07 87 4.97 AL2p-h211.37E−07 76 6.28 AL2p-h22 3.25E−07 61 5.00 AL2p-h23 3.34E−07 76 5.38AL2p-h24 1.15E−06 69 4.36 AL2p-h25 1.53E−07 90 7.45 AL2p-h26 9.53E−08 787.25 AL2p-h27 1.20E−07 78 7.23 AL2p-h28 N.B. 79 5.59 AL2p-h29 N.B. 825.80 AL2p-h30 1.81E−07 88 6.01 AL2p-h31 1.16E−07 83 5.04 AL2p-h321.44E−07 81 5.60 AL2p-h33 2.25E−07 74 6.21 AL2p-h34 1.42E−07 84 6.92AL2p-h35 1.27E−07 69 6.81 AL2p-h36 N.B. 85 4.13 AL2p-h42 1.41E−07 799.29 AL2p-h43 1.34E−07 91 8.65 AL2p-h44 1.80E−07 80 7.29 AL2p-h471.61E−07 93 9.28 AL2p-h50 1.80E−07 78 6.36 AL2p-h59 1.30E−07 69 7.06AL2p-h76 8.30E−08 86 6.52 AL2p-h77 9.39E−08 83 7.14 AL2p-h90 6.12E−08126 4.35 In Table 1, “N.B.” refers to no binding; and “FOB” refers tofold over background.

Example 2: Affinity Matured AL2p Antibodies Show Highly ImprovedAffinity

Methods

Affinity maturation of humanized AL2p variants AL2p-h50 and AL2p-h77 wasperformed. Briefly, key amino acid residues in the heavy or light chainwere selectively mutagenized and mutants that improved binding wereselected through additional rounds of screening. This processsimultaneously improves specificity, species cross-reactivity, anddevelopability profiles, allowing precise tuning of properties criticalfor the desired mechanism of action, potency in biological assays, andpre-clinical modeling. Delivery characterizations included Forte Bio andMSD affinity measurements, cell binding and several developabilityassays. After the first round of affinity maturation, antibodies withelevated affinity also displayed elevated polyspecific reactivity (PSR),which is used to determine unspecific binding of the antibody. Thus, asecond round of affinity maturation was performed to improve affinitywithout elevating PSR.

The affinity of the affinity matured anti-TREM2 antibodies wasdetermined by measuring their K_(D), as well as on- and off-rates byForteBio OctetRed as previously described by Estep et al., Mabs 2013:5(2):270-278. Briefly, IgGs were loaded on-line onto AHQ sensors.Sensors were equilibrated off-line in assay buffer for 30 minutes andthen monitored on-line for 60 seconds for baseline establishment. Foravid binding measurement, sensors with loaded IgGs were exposed to 100nM antigen (human or cynomolgus monkey TREM2 Fc fusion using the entireTREM2 ECD; only one Fc arm was fused to TREM2) for 3 minutes, afterwardsthey were transferred to assay buffer for 3 minutes for off-ratemeasurement. Monovalent binding measurements were obtained by loadinghuman TREM2 Fc fusion antigens to AHQ sensor and followed by exposure to−100 nM TREM2 antibody Fab. Kinetics data were fit using a 1:1 bindingmodel in the data analysis software provided by ForteBio. Assay was runat room temperature (25° C.).

To examine cell binding of affinity matured anti-TREM2 antibodies, bothprimary human monocyte derived dendritic cells and recombinant, humanTREM2 expressing cells were utilized. For the latter, BW5147.G.1.4(ATCC® TIB48™) and HEK293T cells stably expressing human TREM2 togetherwith Dap12 using viral infection were established. For primary humanmonocyte derived dendritic cells, human monocytes were isolated fromwhole blood using RosetteSep Human monocyte enrichment cocktail(Stemcell technologies) and Ficoll centrifugation per manufacturerprotocols. After lysing red blood cells with ACK lysing buffer,monocytes were resuspended in complete media (RPMI, 10% FBS, Pen/Strep,L-glutamine, HEPES, non-essential amino acid, Sodium pyruvate) with 100ng/ml human GM-CSF (hu-GMCSF) and human IL-4 (hu-IL-4) to differentiatedendritic cells for 6 days.

Cells were harvested by trypsinization (Hek293T) or scraping (BW anddendritic cells), washed in PBS, counted and plated on 96-well U bottomplates at 1×10⁵ cells/well. The plates were spun at 1,400 rpm for 3minutes and primary TREM2 or control antibodies were added in FACSbuffer (PBS+2% FBS) and incubated on ice for one hour. Cells weresubsequently centrifuged as before and washed thrice with FACS buffer.Cells were then incubated with anti-human PE conjugated secondaryantibody (BD Biosciences) in FACS buffer for 30 minutes on ice. Cellswere again washed thrice with FACS buffer and analyzed on a BD FACSCanto or an Intellicyt Flow Cytometer. Binding was measured as meanfluorescence intensity in the APC channel.

Results

Two rounds of affinity maturation were performed on AL2p variantsAL2p-h50 and AL2p-h77. In total, 57 affinity matured clones wereselected from the AL2p-h50 lineage and 4 clones from the AL2p-h77lineage. The heavy chain variable region HVR sequences of the antibodiesare depicted in Tables 2A to 2C. The light chain variable region HVRsequences of the antibodies are depicted in Tables 3A to 3C. The heavychain framework regions of the antibodies are depicted in Tables 4A to4D. The light chain framework regions of the antibodies are depicted inTables 5A to 5D. The heavy chain variable region sequences of theantibodies are depicted in Table 6A. The heavy chain sequences of AL2pvariant antibodies are depicted in Table 6B. The light chain variableregion sequences of the antibodies are depicted in Table 7A. The lightchain sequences of AL2p variant antibodies are depicted in Table 7B.

TABLE 2A Heavy chain HVR H1 sequences of anti-TREM2  antibodies SEQ IDAb HVR H1 NO: AL2p-h50, AL2p-2, AL2p-3,  YAFSSSWMN 124AL2p-4, AL2p-5, AL2p-6,  AL2p-33, AL2p-h77, and  AL2p-36AL2p-29, AL2p-30, AL2p-31,  YAFSSQWMN 132 AL2p-37, AL2p-58, AL2p-60,AL2p-61, and AL2p-62 AL2p-10, AL2p-11, AL2p-45,  YAFSSDWMN 136AL2p-46, AL2p-47, AL2p-48, and AL2p-49 AL2p-7 and AL2p-8 YAFSLSWMN 157AL2p-9 YAFSRSWMN 158 AL2p-12, AL2p-13, AL2p-14,  YAFSSHWMN 159AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26,AL2p-27, AL2p-28, AL2p-38,  AL2p-39, AL2p-40, AL2p-41,AL2p-42, AL2p-43, AL2p-44,  AL2p-50, AL2p-51, AL2p-52,AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, and  AL2p-59 AL2p-32YAFSSEWMN 160 AL2p-35 YAFWSSWMN 161 Formula I YAFX₁X₂X₃WMN 121X₁ is S or W X₂ is S, L, or R X₃ is S, D, H,  Q, or E

TABLE 2B Heavy chain HVR H2 sequences of anti-TREM2 antibodies SEQ ID AbHVR H2 NO: AL2p-h50, AL2p-5, AL2p-  RIYPGDGDTNYAQKFQG 1256, AL2p-9, AL2p-10,  AL2p-14, AL2p-15, AL2p- 29, AL2p-32, AL2p-33, AL2p-h77, and AL2p-35 AL2p-31 and AL2p-60 RIYPGGGDTNYARKFQG 133AL2p-37 and AL2p-58 RIYPGGGDTNYAGKFQG 135 AL2p-47, AL2p-48, RIYPGEGDTNYARKFHG 137 AL2p-49 AL2p-45, AL2p-46, and  RIYPGEGDTNYARKFQG141 AL2p-61 AL2p-62 RIYPGEGDTNYAGKFQG 143 AL2p-2 and AL2p-24RIYPGGGDTNYAQKFQG 162 AL2p-3 RIYPGEGDTNYAQKFQG 163 AL2p-4 and AL2p-27RIYPGQGDTNYAQKFQG 164 AL2p-7 and AL2p-16 RIYPGDGDTNYAQKFRG 165AL2p-8, AL2p-11, AL2p-  RIYPGDGDTNYARKFQG 166 19, AL2p-20, and AL2p- 36AL2p-12 RIYPGDGDTNYAHKFQG 167 AL2p-13 RIYPGDGDTNYAQKFKG 168 AL2p-17RIYPGDGDTNYAQKRQG 169 AL2p-18 RIYPGDGDTNYAQKWQG 170 AL2p-21 and AL2p-30RIYPGDGDTNYAWKFQG 171 AL2p-22 RIYPGDGDTNYAYKFQG 172 AL2p-23RIYPGDGQTNYAQKRQG 173 AL2p-25, AL2p-38, AL2p-  RIYPGGGDTNYAQKFRG 17439, and AL2p-40 AL2p-26 RIYPGGGDTNYAQKRQG 175 AL2p-28 RIYPGVGDTNYAQKFQG176 AL2p-41 and AL2p-42 RIYPGEGDTNYAQKFRG 177 AL2p-43 and AL2p-44RIYPGGGDTNYARKFRG 178 AL2p-50, AL2p-51, AL2p-  RIYPGEGDTNYAQKFHG 17952, AL2p-53, AL2p-54, AL2p-55, AL2p-56, and AL2p-57 AL2p-59RIYPGEGQTNYAQKRQG 180 Formula II RIYPGX₁GX₂TNYAX₃KX₄X₅G 122X₁ is D, G, E, Q, or V X₂ is D or Q X₃ is Q, R, H, W, Y,  or GX₄ is F, R, or W X₅ is Q, R, K, or H

TABLE 2C Heavy chain HVR H3 sequences of anti-TREM2  antibodies SEQ IDAb HVR H3 NO: AL2p-h50, AL2p-2, AL2p-3,  ARLLRNQPGESYAMDY 126AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-17, AL2p-19,AL2p-20, AL2p-21, AL2p-22,  AL2p-23, AL2p-24, AL2p-25,AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-37, AL2p-50, AL2p-51,AL2p-52, AL2p-53, AL2p-58,  AL2p-59, AL2p-60, AL2p-61, and AL2p-62AL2p-45, AL2p-46, AL2p-47,  ARLLRNKPGESYAMDY 138AL2p-48, AL2p-49, AL2p-54, AL2p-55, AL2p-56, and  AL2p-57AL2p-8 and AL2p-18 ARLLRNQPGSSYAMDY 181 AL2p-9, AL2p-16, AL2p-36, ARLLRNQPGASYAMDY 182 AL2p-38, AL2p-39, AL2p-40,AL2p-41, AL2p-42, AL2p-43,  and AL2p-44 AL2p-35 ARLLRNQPGESYAHDY 183Formula III ARLLRNX₁PGX₂SYAX₃DY 123 X₁ is Q or K X₂ is E, S, or AX₃ is M or H

TABLE 3A Light chain HVR L1 sequences of anti-TREM2 antibodies SEQ ID AbHVR L1 NO: AL2p-h50, AL2p-2, AL2p-3,  RSSQSLVHSNGYTYLH 130AL2p-4, AL2p-10, AL2p-12, AL2p-31, AL2p-32, AL2p-h77, AL2p-35, AL2p-36,   and AL2p-37 AL2p-45, AL2p-47, AL2p-50, RTSQSLVHSNAYTYLH 139 AL2p-52, AL2p-55, and  AL2p-56 AL2p-61 and AL2p-62RSSQSLVHSNQYTYLH 142 AL2p-5, AL2p-58, and  RSSQSLVHSNRYTYLH 144 AL2p-60AL2p-6 RSSQSLVHSNWYTYLH 184 AL2p-7, AL2p-8, AL2p-13,  RSSQSLIHSNGYTYLH185 and AL2p-26 AL2p-9, AL2p-16, AL2p-18,  RTSQSLVHSNGYTYLH 186AL2p-20, AL2p-23, AL2p-25, AL2p-28, and AL2p-33AL2p-11, AL2p-14, AL2p-17,  RSSRSLVHSNGYTYLH 187AL2p-19, AL2p-22, AL2p-24, AL2p-27, and AL2p-29 AL2p-15, AL2p-21, and RSSSSLVHSNGYTYLH 188 AL2p-30 AL2p-38 and AL2p-43 RSSRSLVHSNRYTYLH 189AL2p-39 and AL2p-41 RSSRSLVHSNQYTYLH 190 AL2p-40, AL2p-42, and RTSRSLVHSNRYTYLH 191 AL2p-44 AL2p-46, AL2p-48, AL2p-49, RTSQSLVHSNQYTYLH 192 AL2p-51, AL2p-53, AL2p-54, AL2p-57, and AL2p-59Formula IV RX₁SX₂SLX₃HSNX₄YTYLH 127 X₁ is S or T X₂ is Q, R, or SX₃ is V or I X₄ is G, R, W, Q,  or A

TABLE 3B Light chain HVR L2 sequences of  anti-TREM2 antibodies SEQ IDAb HVR L2 NO: AL2p-h50, AL2p-2, AL2p-3,  KVSNRFS 131AL2p-4, AL2p-5, AL2p-6, AL2p-14, AL2p-24, AL2p-29,  AL2p-h77, AL2p-35,AL2p-36, AL2p-37, AL2p-58,  and AL2p-62 AL2p-7, AL2p-8, AL2p-10, KVSNRRS 134 AL2p-12, AL2p-13, AL2p-22, AL2p-26, AL2p-31, AL2p-32, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-60, and AL2p-61 AL2p-9, AL2p-11, AL2p-16,  KVSNRVS 140AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-23, AL2p-25, AL2p-27, AL2p-28, AL2p-33, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, and AL2p-59AL2p-15, AL2p-21, and AL2p-30 KVSNRKS 193 Formula V KVSNRX₁S 128X₁ is F,  R, V, or K

TABLE 3C Light chain HVR L3 sequences of anti-TREM2 antibodies SEQ ID AbHVR L3 NO: AL2p-h50, AL2p-2, AL2p-3, AL2p-4, SQSTRVPYT 129AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12,AL2p-13, AL2p-14, AL2p-15, AL2p-16,  AL2p-17, AL2p-18, AL2p-19, AL2p-20,AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36,AL2p-37, AL2p-38, AL2p-39, AL2p-40,  AL2p-41, AL2p-42, AL2p-43, AL2p-44,AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58, AL2p-59, AL2p-60,AL2p-61, and AL2p-62

TABLE 4A Heavy chain framework 1 sequences of anti-TREM2 antibodies SEQID Ab VH FR1 NO: AL2p-h50, AL2p-2,  QVQLVQSGAEVKKPGSSVKVSCKASG  9AL2p-3, AL2p-4,  AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12,  AL2p-13, AL2p-14, AL2p-15, AL2p-16,AL2p-17, AL2p-18,  AL2p-19, AL2p-20, AL2p-21, AL2p-22,AL2p-23, AL2p-24,  AL2p-25, AL2p-26, AL2p-27, AL2p-28,AL2p-29, AL2p-30,  AL2p-31, AL2p-32, AL2p-38, AL2p-39,AL2p-40, AL2p-41,  AL2p-42, AL2p-43, AL2p-44, AL2p-45,AL2p-46, AL2p-47,  AL2p-48, AL2p-50, AL2p-51, AL2p-54,AL2p-59, AL2p-60, and AL2p-61 AL2p-33, AL2p-49, EVQLVQSGAEVKKPGSSVKVSCKASG 10 AL2p-52, AL2p-53, AL2p-55, AL2p-56, andAL2p-57 AL2p-h77, AL2p-35,  QVQLVQSGAEVKKPGASVKVSCKASG 11AL2p-36, AL2p-37, AL2p-58, and AL2p-62

TABLE 4B Heavy chain framework 2 sequences of  anti-TREM2 antibodies SEQID Ab VH FR2 NO: AL2p-h50, AL2p-2, AL2p-3,  WVRQAPGQGLEWMG 12AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12,  AL2p-13, AL2p-14, AL2p-15,AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21,AL2p-22, AL2p-23, AL2p-24,  AL2p-25, AL2p-26, AL2p-27,AL2p-28, AL2p-29, AL2p-30,  AL2p-31, AL2p-32, AL2p-33, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52,  AL2p-53, AL2p-54, AL2p-55,AL2p-56, AL2p-57, AL2p-59,  AL2p-60, and AL2p-61AL2p-h77, AL2p-35, AL2p-36,  WVRQAPGQRLEWIG 13AL2p-37, AL2p-58, and AL2p-62

TABLE 4C Heavy chain framework 3 sequences of  anti-TREM2 antibodies SEQID Ab VH FR3 NO: AL2p-h50, AL2p-2, AL2p-3, RVTITADESTSTAYM 14AL2p-4, AL2p-5, AL2p-6, ELSSLRSEDTAVYYC AL2p-7, AL2p-8, AL2p-9,AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15,AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21,AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27,AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33,AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43,AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49,AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55,AL2p-56, AL2p-57, AL2p-59, AL2p-60, and AL2p-61 AL2p-h77, AL2p-35, AL2p-RVTITADTSASTAYM 15 36, AL2p-37, AL2p-58, and ELSSLRSEDTAVYYC AL2p-62

TABLE 4D Heavy chain framework 4 sequences of  anti-TREM2 antibodies SEQID Ab VH FR4 NO: AL2p-h50, AL2p-2, AL2p-3,  WGQGTLVTVSS 16AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16, AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-h77, AL2p-35, AL2p-36,  AL2p-37, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42,  AL2p-43, AL2p-44, AL2p-45,AL2p-46, AL2p-47, AL2p-48,  AL2p-49, AL2p-50, AL2p-51,AL2p-52, AL2p-53, AL2p-54,  AL2p-55, AL2p-56, AL2p-57,AL2p-58, AL2p-59, AL2p-60,  AL2p-61, and AL2p-62

TABLE 5A Light chain framework 1 sequences of anti-TREM2 antibodies SEQID Ab VL FR1 NO: AL2p-h50, AL2p-2,  DVVMTQTPLSLSVTPGQPASISC 17AL2p-3, AL2p-4, AL2p-5, AL2p-6,  AL2p-11, AL2p-17, AL2p-19, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49,  AL2p-50, AL2p-51,AL2p-52, AL2p-53,  AL2p-54, AL2p-55, AL2p-56, and AL2p-57AL2p-7, AL2p-8,  GVVMTQTPLSLSVTPGQPASISC 18 AL2p-9, AL2p-10,AL2p-12, AL2p-13,  AL2p-14, AL2p-15, AL2p-16, AL2p-18, AL2p-20, AL2p-21, AL2p-22, AL2p-23,  AL2p-24, AL2p-25,AL2p-26, AL2p-27,  AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-38, AL2p-39, AL2p-40,  AL2p-41, AL2p-42,AL2p-43, AL2p-44,  AL2p-59, AL2p-60, and AL2p-61 AL2p-33GVVMAQTPLSLSVTPGQPASISC 19 AL2p-h77, AL2p-35,  DVVMTQSPDSLAVSLGERATINC20 AL2p-36, AL2p-37, AL2p-58, and AL2p-62

TABLE 5B Light chain framework 2 sequences of  anti-TREM2 antibodies SEQID Ab VL FR2 NO: AL2p-h50, AL2p-2, AL2p-3,  WYLQKPGQSPQLLIY 21AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12,  AL2p-13, AL2p-14, AL2p-15,AL2p-16, AL2p-17, AL2p-18,  AL2p-19, AL2p-20, AL2p-21,AL2p-22, AL2p-23, AL2p-24,  AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46,  AL2p-47, AL2p-48, AL2p-49,AL2p-50, AL2p-51, AL2p-52,  AL2p-53, AL2p-54, AL2p-55,AL2p-56, AL2p-57, AL2p-59,  AL2p-60, and AL2p-61AL2p-h77, AL2p-35, AL2p-36,  WYQQKPGQSPKLLIY 22AL2p-37, AL2p-58, and AL2p-62

TABLE 5C Light chain framework 3 sequences of  anti-TREM2 antibodies SEQID Ab VL FR3 NO: AL2p-h50, AL2p-2, GVPDRFSGSGSGTDFTLKI 23AL2p-3, AL2p-4,  SRVEAEDVGVYYC AL2p-5, AL2p-6, AL2p-7, AL2p-8,AL2p-9, AL2p-10,  AL2p-11, AL2p-12, AL2p-13, AL2p-14, AL2p-15, AL2p-16,AL2p-17, AL2p-18, AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24,AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32,AL2p-33, AL2p-38, AL2p-39, AL2p-40, AL2p-41, AL2p-42, AL2p-43, AL2p-44,AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52,AL2p-53, AL2p-54, AL2p-55, AL2p-56, AL2p-57, AL2p-58,AL2p-59, AL2p-60, and AL2p-61 AL2p-h77, AL2p-35, GVPDRFSGSGSGTDFTLTI 24AL2p-36, AL2p-37, and SSLQAEDVAVYYC AL2p-62

TABLE 5D Light chain framework 4 sequences of  anti-TREM2 antibodies SEQID Ab VL FR4 NO: AL2p-h50, AL2p-2, AL2p-3,  FGQGTKLEIK 25AL2p-4, AL2p-5, AL2p-6, AL2p-7, AL2p-8, AL2p-9, AL2p-10, AL2p-11, AL2p-12,  AL2p-13, AL2p-14, AL2p-15,AL2p-16, AL2p-17, AL2p-18,  AL2p-19, AL2p-20, AL2p-21, AL2p-22, AL2p-23, AL2p-24, AL2p-25, AL2p-26, AL2p-27, AL2p-28, AL2p-29, AL2p-30, AL2p-31, AL2p-32, AL2p-33,AL2p-38, AL2p-39, AL2p-40,  AL2p-41, AL2p-42, AL2p-43, AL2p-44, AL2p-45, AL2p-46, AL2p-47, AL2p-48, AL2p-49, AL2p-50, AL2p-51, AL2p-52, AL2p-53, AL2p-54, AL2p-55,AL2p-56, AL2p-57, AL2p-58,  AL2p-59, AL2p-60, and AL2p-61AL2p-h77, AL2p-35, AL2p-36,  FGGGTKVEIK 26 AL2p-37, and AL2p-62

TABLE 6A Heavy chain variable region sequences of  anti-TREM2 antibodiesSEQ ID Ab HCVR NO: AL2p-h50,  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSSWM 27AL2p-5,   NWVRQAPGQGLEWMGRIYPGDGDTNYAQKFQGR andVTITADESTSTAYMELSSLRSEDTAVYYCARLLRN AL2p-6 QPGESYAMDYWGQGTLVTVSS AL2p-2QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSSWM 28 NWVRQAPGQGLEWMGRIYPGGGDTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLLRN QPGESYAMDYWGQGTLVTVSS AL2p-3QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSSWM 29 NWVRQAPGQGLEWMGRIYPGEGDTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLLRN QPGESYAMDYWGQGTLVTVSS AL2p-4QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSSWM 30 NWVRQAPGQGLEWMGRIYPGQGDTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLLRN QPGESYAMDYWGQGTLVTVSS AL2p-7QVQLVQSGAEVKKPGSSVKVSCKASGYAFSLSWM 31 NWVRQAPGQGLEWMGRIYPGDGDTNYAQKFRGRVTITADESTSTAYMELSSLRSEDTAVYYCARLLRN QPGESYAMDYWGQGTLVTVSS AL2p-8QVQLVQSGAEVKKPGSSVKVSCKASGYAFSLSWM 32 NWVRQAPGQGLEWMGRIYPGDGDTNYARKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLLRN QPGSSYAMDYWGQGTLVTVSS AL2p-9QVQLVQSGAEVKKPGSSVKVSCKASGYAFSRSWM 33 NWVRQAPGQGLEWMGRIYPGDGDTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLLRN QPGASYAMDYWGQGTLVTVSS AL2p-10QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDW 34 MNWVRQAPGQGLEWMGRIYPGDGDTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-11QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDW 35 MNWVRQAPGQGLEWMGRIYPGDGDTNYARKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-12QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 36 MNWVRQAPGQGLEWMGRIYPGDGDTNYAHKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-13QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 37 MNWVRQAPGQGLEWMGRIYPGDGDTNYAQKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-14QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 38 andMNWVRQAPGQGLEWMGRIYPGDGDTNYAQKFQ AL2p-15GRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-16QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 39 MNWVRQAPGQGLEWMGRIYPGDGDTNYAQKFRGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGASYAMDYWGQGTLVTVSS AL2p-17QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 40 MNWVRQAPGQGLEWMGRIYPGDGDTNYAQKRQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-18QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 41 MNWVRQAPGQGLEWMGRIYPGDGDTNYAQKWQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGSSYAMDYWGQGTLVTVSS AL2p-19QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 42 andMNWVRQAPGQGLEWMGRIYPGDGDTNYARKFQ AL2p-20GRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-21QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 43 MNWVRQAPGQGLEWMGRIYPGDGDTNYAWKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-22QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 44 MNWVRQAPGQGLEWMGRIYPGDGDTNYAYKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-23QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 45 MNWVRQAPGQGLEWMGRIYPGDGQTNYAQKRQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-24QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 46 MNWVRQAPGQGLEWMGRIYPGGGDTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-25QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 47 MNWVRQAPGQGLEWMGRIYPGGGDTNYAQKFRGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-26QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 48 MNWVRQAPGQGLEWMGRIYPGGGDTNYAQKRQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-27QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 49 MNWVRQAPGQGLEWMGRIYPGQGDTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-28QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 50 MNWVRQAPGQGLEWMGRIYPGVGDTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-29QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSQW 51 MNWVRQAPGQGLEWMGRIYPGDGDTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p -30QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSQW 52 MNWVRQAPGQGLEWMGRIYPGDGDTNYAWKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-31, QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSQW 53 AL2p-60,MNWVRQAPGQGLEWMGRIYPGGGDTNYARKFQ and GRVTITADESTSTAYMELSSLRSEDTAVYYCARLLAL2p-h31 RNQPGESYAMDYWGQGTLVTVSS AL2p-32QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSEWM 54 NWVRQAPGQGLEWMGRIYPGDGDTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLLRN QPGESYAMDYWGQGTLVTVSS AL2p-33EVQLVQSGAEVKKPGSSVKVSCKASGYAFSSSWM 55 NWVRQAPGQGLEWMGRIYPGDGDTNYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLLRN QPGESYAMDYWGQGTLVTVSS AL2p-h77, QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSW 56 AL2p-h26,  MNWVRQAPGQRLEWIGRIYPGDGDTNYAQKFQG andRVTITADTSASTAYMELSSLRSEDTAVYYCARLLR AL2p-h90 NQPGESYAMDYWGQGTLVTVSSAL2p-35 QVQLVQSGAEVKKPGASVKVSCKASGYAFWSSW 57MNWVRQAPGQRLEWIGRIYPGDGDTNYAQKFQG RVTITADTSASTAYMELSSLRSEDTAVYYCARLLRNQPGESYAHDYWGQGTLVTVSS AL2p-36 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSW 58MNWVRQAPGQRLEWIGRIYPGDGDTNYARKFQG RVTITADTSASTAYMELSSLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSS AL2p-37  QVQLVQSGAEVKKPGASVKVSCKASGYAFSSQW 59 andMNWVRQAPGQRLEWIGRIYPGGGDTNYAGKFQG AL2p-58RVTITADTSASTAYMELSSLRSEDTAVYYCARLLR NQPGESYAMDYWGQGTLVTVSS AL2p-38, QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 60 AL2p-39,MNWVRQAPGQGLEWMGRIYPGGGDTNYAQKFR and GRVTITADESTSTAYMELSSLRSEDTAVYYCARLLAL2p-40 RNQPGASYAMDYWGQGTLVTVSS AL2p-41  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 61 andMNWVRQAPGQGLEWMGRIYPGEGDTNYAQKFRG AL2p-42RVTITADESTSTAYMELSSLRSEDTAVYYCARLLR NQPGASYAMDYWGQGTLVTVSS AL2p-43  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 62 andMNWVRQAPGQGLEWMGRIYPGGGDTNYARKFR AL2p-44GRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGASYAMDYWGQGTLVTVSS AL2p-45  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDW 63 andMNWVRQAPGQGLEWMGRIYPGEGDTNYARKFQG AL2p-46RVTITADESTSTAYMELSSLRSEDTAVYYCARLLR NKPGESYAMDYWGQGTLVTVSS AL2p-47  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDW 64 andMNWVRQAPGQGLEWMGRIYPGEGDTNYARKFHG AL2p-48RVTITADESTSTAYMELSSLRSEDTAVYYCARLLR NKPGESYAMDYWGQGTLVTVSS AL2p-49EVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDWM 65 NWVRQAPGQGLEWMGRIYPGEGDTNYARKFHGRVTITADESTSTAYMELSSLRSEDTAVYYCARLLRN KPGESYAMDYWGQGTLVTVSS AL2p-50  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 66 andMNWVRQAPGQGLEWMGRIYPGEGDTNYAQKFH AL2p-51GRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-52  EVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWM 67 andNWVRQAPGQGLEWMGRIYPGEGDTNYAQKFHGR AL2p-53VTITADESTSTAYMELSSLRSEDTAVYYCARLLRN QPGESYAMDYWGQGTLVTVSS AL2p-54QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 68 MNWVRQAPGQGLEWMGRIYPGEGDTNYAQKFHGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNKPGESYAMDYWGQGTLVTVSS AL2p-55, EVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHWM 69 AL2p-56,NWVRQAPGQGLEWMGRIYPGEGDTNYAQKFHGR andVTITADESTSTAYMELSSLRSEDTAVYYCARLLRN AL2p-57 KPGESYAMDYWGQGTLVTVSSAL2p-61 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSQW 70MNWVRQAPGQGLEWMGRIYPGEGDTNYARKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS AL2p-62 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSQW 71MNWVRQAPGQRLEWIGRIYPGEGDTNYAGKFQG RVTITADTSASTAYMELSSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSS AL2p-h19  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSSWM 72and NWVRQAPGQGLEWMGRIYPGDGDTNYAQKFQGR AL2p-h35ATITADTSTSTAYMELSSLRSEDTAVYYCARLLRN QPGESYAMDYWGQGTLVTVSS AL2p-h21QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSW 73 MNWVRQAPGQGLEWMGRIYPGDGDTNYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARL LRNQPGESYAMDYWGQGTLVTVSS AL2p-h22QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSW 74 MNWVRQAPGQGLEWIGRIYPGDGDTNYAQKFQGRVTMTADTSTSTVYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-h23QVQLVQSGAEVKKPGASLKISCKASGYAFSSSWM 75 NWVRQAPGQGLEWIGRIYPGDGDTNYAQKFQGRATLTADTSTSTAYMELSSLRSEDTAVYYCARLLRN QPGESYAMDYWGQGALVTVSS AL2p-h24QVQLVQSGAEVVKPGASLKISCKASGYAFSSSWM 76 NWVRQAPGQGLEWIGRIYPGDGDTNYNQKFQGRATLTADTSTSTAYMELSSLRSEDTAVYFCARLLRN QPGESYAMDYWGQGALVTVSS AL2p-h25QVQLVQSGAEVKKPGASLKISCKASGYAFSSSWM 77 NWVRQAPGQGLEWIGRIYPGDGDTNYNGEFRVRATLTADTSTSTAYMELSSLRSEDTAVYYCARLLRNQ PGESYAMDYWGQGALVTVSS AL2p-h27QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSW 78 MNWVRQAPGQGLEWIGRIYPGDGDTNYNGEFRVRATLTADTSTSTAYMELSSLRSEDTAVYFCARLLR NQPGESYAMDYWGQGTLVTVSS AL2p-h28QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSW 79 MNWVRQAPGQGLEWIGRIYPGDGDTNYAQKFQGRATLTADTSTSTAYMELSSLRSEDTAVYFCARLLR NQPGESYAMDYWGQGTLVTVSS AL2p-h29QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSW 80 MNWVRQAPGQGLEWIGRIYPGDGDTNYAQKFQGRATMTADTSTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-h30QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSW 81 MNWVRQAPGQGLEWMGRIYPGDGDTNYAQKFQGRVTMTADTSTSTAYMELSSLRSEDTAVYYCARL LRNQPGESYAMDYWGQGTLVTVSS AL2p-h32QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSSWM 82 NWVRQAPGQGLEWIGRIYPGDGDTNYNGEFRVRATLTADTSTTTAYMELSSLRSEDTAVYFCARLLRNQ PGESYAMDYWGQGTLVTVSS AL2p-h33QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSSWM 83 NWVRQAPGQGLEWIGRIYPGDGDTNYAQKFQGRATLTADTSTTTAYMELSSLRSEDTAVYFCARLLRN QPGESYAMDYWGQGTLVTVSS AL2p-h34QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSSWM 84 NWVRQAPGQGLEWIGRIYPGDGDTNYAQKFQGRATITADTSTSTAYMELSSLRSEDTAVYFCARLLRN QPGESYAMDYWGQGTLVTVSS AL2p-h36EVQLLESGGGLVQPGGSLRLSCAASGYAFSSSWM 85 NWVRQAPGKGLEWIGRIYPGDGDTNYAQKFQGRATISADTSKNTAYLQMNSLRAEDTAVYYCARLLR NQPGESYAMDYWGQGTLVTVSS AL2p-h42 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSW 86 andMNWVRQAPGQRLEWMGRIYPGDGDTNYAQKFQ AL2p-h59GRVTITRDTSASTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS AL2p-h43QVQLVQSGAEVKKPGASLKVSCKASGYAFSSSWM 87 NWVRQAPGQRLEWIGRIYPGDGDTNYNGEFRVRATLTADTSASTAYMELSSLRSEDTAVYFCARLLRNQ PGESYAMDYWGQGTLVTVSS AL2p-h44QVQLVQSGAEVKKPGASLKVSCKASGYAFSSSWM 88 NWVRQAPGQRLEWIGRIYPGDGDTNYAQKFQGRATLTADTSASTAYMELSSLRSEDTAVYFCARLLRN QPGESYAMDYWGQGTLVTVSS AL2p-h47QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSW 89 MNWVRQAPGQGLEWMGRIYPGDGDTNYNGEFRVRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARLLR NQPGESYAMDYWGQGTLVTVSS AL2p-h76QVQLVQSGAEVKKPGASVKVSCKASGYAFSSSW 90 MNWVRQAPGQRLEWIGRIYPGDGDTNYAQKFQGRATITADTSASTAYMELSSLRSEDTAVYFCARLLR NQPGESYAMDYWGQGTLVTVSS AL2p-59QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 91 MNWVRQAPGQGLEWMGRIYPGEGQTNYAQKRQGRVTITADESTSTAYMELSSLRSEDTAVYYCARLL RNQPGESYAMDYWGQGTLVTVSS

TABLE 6B Heavy chain sequences of anti-TREM2 antibodies SEQ ID Ab HC NO:AL2p-58  QVQLVQSGAEVKKPGASVKVSCKASGYAFSSQW 198 huIgG1MNWVRQAPGQRLEWIGRIYPGGGDTNYAGKFQG RVTITADTSASTAYMELSSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK AL2p-58  QVQLVQSGAEVKKPGASVKVSCKASGYAFSSQW 199 huIgG1MNWVRQAPGQRLEWIGRIYPGGGDTNYAGKFQG RVTITADTSASTAYMELSSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG AL2p-58  QVQLVQSGAEVKKPGASVKVSCKASGYAFSSQW 200 huIgG1 MNWVRQAPGQRLEWIGRIYPGGGDTNYAGKFQG PSEGRVTITADTSASTAYMELSSLRSEDTAVYYCARLLR NQPGESYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLS LSPGK AL2p-58 QVQLVQSGAEVKKPGASVKVSCKASGYAFSSQW 201 huIgG1 MNWVRQAPGQRLEWIGRIYPGGGDTNYAGKFQG PSEGRVTITADTSASTAYMELSSLRSEDTAVYYCARLLR NQPGESYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLS LSPG AL2p-47 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDW 202 huIgG1MNWVRQAPGQGLEWMGRIYPGEGDTNYARKFHG RVTITADESTSTAYMELSSLRSEDTAVYYCARLLRNKPGESYAMDYWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK AL2p-47  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDW 203 huIgG1MNWVRQAPGQGLEWMGRIYPGEGDTNYARKFHG RVTITADESTSTAYMELSSLRSEDTAVYYCARLLRNKPGESYAMDYWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG AL2p-47  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDW 204 huIgG1 MNWVRQAPGQGLEWMGRIYPGEGDTNYARKFHG PSEGRVTITADESTSTAYMELSSLRSEDTAVYYCARLLR NKPGESYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLS LSPGK AL2p-47 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSDW 205 huIgG1 MNWVRQAPGQGLEWMGRIYPGEGDTNYARKFHG PSEGRVTITADESTSTAYMELSSLRSEDTAVYYCARLLR NKPGESYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALT SGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELL GGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVS VLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYP SDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLS LSPG AL2p-61 QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSQW 206 huIgG1MNWVRQAPGQGLEWMGRIYPGEGDTNYARKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK AL2p-61  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSQW 207 huIgG1MNWVRQAPGQGLEWMGRIYPGEGDTNYARKFQG RVTITADESTSTAYMELSSLRSEDTAVYYCARLLRNQPGESYAMDYWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG AL2p-40  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 208 huIgG1MNWVRQAPGQGLEWMGRIYPGGGDTNYAQKFR GRVTITADESTSTAYMELSSLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK AL2p-40  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 209 huIgG1MNWVRQAPGQGLEWMGRIYPGGGDTNYAQKFR GRVTITADESTSTAYMELSSLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG AL2p-44  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 210 huIgG1MNWVRQAPGQGLEWMGRIYPGGGDTNYARKFR GRVTITADESTSTAYMELSSLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK AL2p-44  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 211 huIgG1MNWVRQAPGQGLEWMGRIYPGGGDTNYARKFR GRVTITADESTSTAYMELSSLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSSASTKGPSVFPL APSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYI CNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHED PEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISK AKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYS KLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG AL2p-41  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 212 huIgG1MNWVRQAPGQGLEWMGRIYPGEGDTNYAQKFRG RVTITADESTSTAYMELSSLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK AL2p-41  QVQLVQSGAEVKKPGSSVKVSCKASGYAFSSHW 213 huIgG1MNWVRQAPGQGLEWMGRIYPGEGDTNYAQKFRG RVTITADESTSTAYMELSSLRSEDTAVYYCARLLRNQPGASYAMDYWGQGTLVTVSSASTKGPSVFPLA PSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYIC NVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDP EVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKA KGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSK LTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG

TABLE 7A Light chain variable region sequences of  anti-TREM2 antibodiesSEQ ID Ab LCVR NO: AL2p-h50,  DVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNGYTY  92AL2p-2,  LHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSG AL2p-3,TDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL AL2p-4, EIK AL2p-h42, AL2p-h43,AL2p-h44,  and AL2p-h47 AL2p-5 DVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNRYTY  93LHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL EIK AL2p-6DVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNWYT  94YLHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTK LEIK AL2p-7, GVVMTQTPLSLSVTPGQPASISCRSSQSLIHSNGYTY  95 AL2p-8, LHWYLQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSG AL2p-13,TDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL and EIK AL2p-26 AL2p-9, GVVMTQTPLSLSVTPGQPASISCRTSQSLVHSNGYTY  96 AL2p-16,LHWYLQKPGQSPQLLIYKVSNRVSGVPDRFSGSGSG AL2p-18, TDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL AL2p-20, EIK AL2p-23,  AL2p-25,and  AL2p-28 AL2p-10,  GVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNGYTY  97AL2p-12, LHWYLQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSG AL2p-31, TDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL and EIK AL2p-32 AL2p-11, DVVMTQTPLSLSVTPGQPASISCRSSRSLVHSNGYTY  98 AL2p-17, LHWYLQKPGQSPQLLIYKVSNRVSGVPDRFSGSGSG andTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL AL2p-19 EIK AL2p-14, GVVMTQTPLSLSVTPGQPASISCRSSRSLVHSNGYTY  99 AL2p-24, LHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSG andTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL AL2p-29 EIK AL2p-15, GVVMTQTPLSLSVTPGQPASISCRSSSSLVHSNGYTY 100 AL2p-21, LHWYLQKPGQSPQLLIYKVSNRKSGVPDRFSGSGSG andTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL AL2p-30 EIK AL2p-22GVVMTQTPLSLSVTPGQPASISCRSSRSLVHSNGYTY 101LHWYLQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL EIK AL2p-27GVVMTQTPLSLSVTPGQPASISCRSSRSLVHSNGYTY 102LHWYLQKPGQSPQLLIYKVSNRVSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL EIK AL2p-33GVVMAQTPLSLSVTPGQPASISCRTSQSLVHSNGYTY 103LHWYLQKPGQSPQLLIYKVSNRVSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL EIK AL2p-h77,DVVMTQSPDSLAVSLGERATINCRSSQSLVHSNGYT 104 AL2p-35,  YLHWYQQKPGQSPKLLIYKVSNRFSGVPDRFSGSGS AL2p-36,GTDFTLTISSLQAEDVAVYYCSQSTRVPYTFGGGTK AL2p-37, VEIK and AL2p-h76 AL2p-38 GVVMTQTPLSLSVTPGQPASISCRSSRSLVHSNRYTY 105 and LHWYLQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSG AL2p-43TDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL EIK AL2p-39  GVVMTQTPLSLSVTPGQPASISCRSSRSLVHSNQYTY 106 andLHWYLQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSG AL2p-41TDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL EIK AL2p-40, GVVMTQTPLSLSVTPGQPASISCRTSRSLVHSNRYTY 107 AL2p-42, LHWYLQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSG andTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL AL2p-44 EIK AL2p-45, DVVMTQTPLSLSVTPGQPASISCRTSQSLVHSNAYTY 108 AL2p-47, LHWYLQKPGQSPQLLIYKVSNRVSGVPDRFSGSGSG AL2p-50, TDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL AL2p-52, EIK AL2p-55, and AL2p-56AL2p-46,  DVVMTQTPLSLSVTPGQPASISCRTSQSLVHSNQYTY 109 AL2p-48, LHWYLQKPGQSPQLLIYKVSNRVSGVPDRFSGSGSG AL2p-49, TDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL AL2p-51,  EIK AL2p-53, AL2p-54, andAL2p-57 AL2p-61 GVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNQYTY 110LHWYLQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL EIK AL2p-62DVVMTQSPDSLAVSLGERATINCRSSQSLVHSNQYT 111YLHWYQQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCSQSTRVPYTFGGGTK VEIK AL2p-58DVVMTQSPDSLAVSLGERATINCRSSQSLVHSNRYT 112YLHWYQQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTK LEIK AL2p-60GVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNRYTY 113LHWYLQKPGQSPQLLIYKVSNRRSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL EIK AL2p-h19DIVMTQTPLSLSVTPGQPASISCRSSQSLVHSNGYTY 114LHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL EIK AL2p-h21, DVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNGYTY 115 AL2p-h22,LHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSG AL2p-h23,TDFTLKISRVEAEDLGVYFCSQSTRVPYTFGQGTKLE AL2p-h24, IK AL2p-h25,  AL2p-h26,AL2p-h27,  AL2p-h28, AL2p-h29, AL2p-h30,  AL2p-h31, AL2p-h32, AL2p-h33, AL2p-h34, AL2p-h35, AL2p-h36 AL2p-h59DIVMTQSPLSLPVTPGEPASISCRSSQSLVHSNGYTYL 116HWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGGGTKVEI K AL2p-h90DVQMTQSPSSLSASVGDRVTITCRSSQSLVHSNGYT 117YLHWYQQKPGKSPKLLIYKVSNRFSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCSQSTRVPYTFGGGTKV EIK AL2p-59GVVMTQTPLSLSVTPGQPASISCRTSQSLVHSNQYTY 118LHWYLQKPGQSPQLLIYKVSNRVSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKL EIK

TABLE 7B Light chain sequences of anti-TREM2 antibodies SEQ ID Ab LC NO:AL2p-58  DVVMTQSPDSLAVSLGERATINCRSSQSLVHSNRY 214 huIgG1, TYLHWYQQKPGQSPKLLIYKVSNRFSGVPDRFSGS andGSGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQ AL2p-58GTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLL huIgG1 NNFYPREAKVQWKVDNALQSGNSQESVTEQDSK PSEGDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSP VTKSFNRGEC AL2p-47 DVVMTQTPLSLSVTPGQPASISCRTSQSLVHSNAYT 215 huIgG1, YLHWYLQKPGQSPQLLIYKVSNRVSGVPDRFSGSG andSGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQG AL2p-47TKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN huIgG1 NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS PSEGTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC AL2p-61 GVVMTQTPLSLSVTPGQPASISCRSSQSLVHSNQYT 216 huIgG1YLHWYLQKPGQSPQLLIYKVSNRRSGVPDRFSGSG SGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC AL2p-41 GVVMTQTPLSLSVTPGQPASISCRSSRSLVHSNQYT 217 huIgG1YLHWYLQKPGQSPQLLIYKVSNRRSGVPDRFSGSG SGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVT KSFNRGEC AL2p-40 GVVMTQTPLSLSVTPGQPASISCRTSRSLVHSNRYT 218 huIgG1, YLHWYLQKPGQSPQLLIYKVSNRRSGVPDRFSGSG andSGTDFTLKISRVEAEDVGVYYCSQSTRVPYTFGQG AL2p-44TKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLN huIgG1NFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS TYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC

Clones were tested for affinity using OctetRed and a strong increase inmonovalent affinity was observed (Table 8). In addition, clones weretested for binding to cynomolgus monkey TREM2 and all clones were ableto bind monovalently (Table 8). Clones were tested for binding to humanTREM2-expressing BW cells and improved affinity was observed in thissetting as well (Table 8). In addition, antibodies showed increasedbinding to primary human dendritic cells that express human TREM2endogenously (Table 8).

The parental AL2p antibody contains two residues that are subject tode-amidation, a DG in VH-CDR2 and a NG in VL-CDR1. When testing affinitymatured AL2p variant antibodies, five clones with amino acidsubstitutions at these positions were produced: AL2p-2 (DG to GG),AL2p-3 (DG to EG), AL2p-4 (DG to QG), AL2p-5 (NG to NR), AL2p-6 (NG toNW). These variants were confirmed to retain that same affinity as theparental AL2p-h50 antibody (Table 8). Additionally, variants AL2p-38 toAL2p-57 already included amino acid substitutions at these positions,which are DG to GG or EG in VH-CDR2 together with NG to NR or NQ or NAin VL-CDR1. These clones show improved affinity and function compared tothe parental clone, suggesting that the combination of amino acidsubstitutions at these positions does not affect function.

TABLE 8 Summary of binding experiments of AL2p variant antibodiesForteBio ForteBio Fab K_(D) Fab K_(D) ForteBio cyno huTREM2- IgG K_(D)TREM2- cell MFI Fc (M) huTREM2- Fc (M) binding binding mono- Fc (M)mono- huT2 BW to Antibody valent avid valent K_(D) (nM) huDCs AL2p-h501.12E−07 1.19E−09 7.70E−06 3.7 26 AL2p-h77 1.02E−07 1.17E−09 1.84E−073.9 162 AL2p-2 6.33E−08 8.37E−10 1.40E−06 2.2 AL2p-3 1.00E−07 1.19E−094.58E−06 2.3 AL2p-4 1.32E−07 8.17E−10 P.F. 2.1 AL2p-5 9.92E−08 1.00E−094.63E−06 2.0 AL2p-6 2.59E−07 1.06E−09 1.15E−06 4.2 AL2p-7 8.38E−094.27E−10 8.95E−09 1.6 AL2p-8 4.01E−09 3.00E−10 3.10E−09 1.2 310 AL2p-96.44E−09 3.49E−10 5.63E−09 1.1 322 AL2p-10 1.85E−08 8.35E−10 2.77E−083.1 AL2p-11 9.83E−09 5.36E−10 1.02E−08 2.4 AL2p-12 5.86E−09 5.14E−105.25E−09 1.8 AL2p-13 4.80E−09 3.40E−10 4.93E−09 1.5 AL2p-14 4.74E−093.15E−10 4.66E−09 2.1 AL2p-15 8.85E−09 5.38E−10 8.76E−09 2.2 262 AL2p-161.83E−09 2.22E−10 1.36E−09 1.2 327 AL2p-17 4.83E−09 2.55E−10 4.62E−091.4 AL2p-18 3.17E−09 2.29E−10 2.73E−09 1.3 AL2p-19 4.02E−09 3.03E−104.01E−09 1.4 AL2p-20 4.73E−09 3.50E−10 4.72E−09 1.2 AL2p-21 4.15E−093.99E−10 3.84E−09 1.5 AL2p-22 1.58E−09 2.19E−10 1.28E−09 1.5 AL2p-234.35E−09 3.34E−10 4.16E−09 1.2 AL2p-24 2.10E−09 2.33E−10 1.63E−09 1.7AL2p-25 2.34E−09 2.20E−10 1.76E−09 1.7 AL2p-26 3.15E−09 2.01E−102.69E−09 1.1 296 AL2p-27 1.99E−09 2.74E−10 1.82E−09 1.5 AL2p-28 7.60E−094.17E−10 7.91E−09 2.2 AL2p-29 6.38E−09 4.03E−10 6.47E−09 1.3 AL2p-306.50E−09 3.77E−10 5.66E−09 1.2 AL2p-31 4.03E−09 3.17E−10 3.44E−09 1.0288 AL2p-32 3.60E−08 1.12E−09 3.48E−08 2.8 AL2p-33 1.03E−08 8.89E−108.84E−10 4.5 AL2p-35 2.84E−08 1.85E−09 2.46E−08 3.6 130 AL2p-36 1.21E−084.95E−10 7.38E−09 1.7 240 AL2p-37 2.38E−08 7.79E−10 1.61E−08 2.9 194AL2p-38 6.23E−10 3.70E−10 4.79 499 AL2p-39 6.31E−10 3.46E−10 1.53 590AL2p-40 6.02E−10 3.70E−10 2.27 547 AL2p-41 7.24E−10 3.52E−10 1.31 534AL2p-42 8.29E−10 3.12E−10 1.91 662 AL2p-43 4.93E−10 3.60E−10 5.01 1035AL2p-44 4.10E−10 2.71E−10 4.18 1467 AL2p-45 1.78E−08 2.09E−08 1.54 318AL2p-46 1.30E−08 1.61E−08 1.33 187 AL2p-47 1.48E−08 1.63E−08 1.09 372AL2p-48 1.12E−08 1.49E−08 1.40 408 AL2p-49 1.16E−08 1.41E−08 1.15 413AL2p-50 2.39E−08 3.61E−08 1.80 235 AL2p-51 2.12E−08 2.72E−08 1.92 195AL2p-52 2.70E−08 2.80E−08 2.42 224 AL2p-53 2.11E−08 3.13E−08 1.72 159AL2p-54 1.39E−08 1.68E−08 2.30 235 AL2p-55 1.85E−08 2.26E−08 2.05 141AL2p-56 1.87E−08 1.88E−08 2.01 155 AL2p-57 1.78E−08 1.76E−08 1.83 152AL2p-59 3.85E−09 3.95E−09 AL2p-61 3.73E−06 3.84E−09 AL2p-62 2.11E−081.94E−08 AL2p-58 1.33E−08 1.24E−08 0.51

In Table 8, experiments for clones AL2p-2 to AL2p-37 were performedseparately from experiments characterizing AL2p-38 to AL2p-57. Bindingto human dendritic cells (DC's) was performed on different donors forthese two sets of antibodies and because there is a large donor to donorvariability in TREM2 expression, MFI values cannot be directly comparedacross donors. P.F.=poor fit; MFI=mean fluorescence intensity.

Example 3: Affinity Matured AL2p Antibodies Show Highly ImprovedFunction

Methods

The ability of plate-bound, full-length anti-TREM2 antibodies toactivate human TREM2-dependent genes was evaluated using a luciferasereporter gene under the control of an NFAT (nuclear factor of activatedT-cells) promoter. The cell line BW5147.G.1.4, derived from mouse thymuslymphoma T lymphocytes, was infected with a human TREM2/DAP12 fusionprotein, and with Cignal Lenti NFAT-Luciferase virus (Qiagen). To testthe antibodies, plate bound, anti-TREM2 and isotype control antibodieswere dissolved in PBS, plated on tissue culture plates at aconcentration of 10 μg/ml and incubated overnight at 4° C. to allow theantibodies to absorb to the plate. After washing of the plates, cellswere plated on the plate-bound antibodies and incubated for 4 to 6 hoursat 37° C. To test antibodies in solution, they were added to the cultureplates together with the cells and incubated for 4 to 6 hours at 37° C.Luciferase activity was measured by adding OneGlo Reagent (Promega) toeach well and incubating for 3 minutes at room temperature on a plateshaker. Luciferase signal was measured using a BioTek plate reader.

The ability of soluble, full-length anti-TREM2 antibodies to change theactivity of natural ligands of human TREM2 was evaluated using aluciferase reporter gene assay as well. Cells were incubated for 4 to 6hours, together with soluble anti-TREM2 and isotype control antibodies,on plates that were pre-coated with phosphatidylserine (lipid wasdissolved and titrated in methanol, added to the plates and methanol wasallowed to evaporate overnight). Cells were lysed and luciferaseactivity was measured by adding OneGlo Reagent (Promega) to each welland incubating for 3 minutes at room temperature on a plate shaker.Luciferase signal was measured using a BioTek plate reader.

To assess viability of human dendritic cells and macrophages humanmonocytes were isolated from whole blood using RosetteSep Human monocyteenrichment cocktail (Stemcell technologies) and Ficoll centrifugationper manufacturer protocols. After lysing red blood cells with ACK lysingbuffer, monocytes were resuspended in complete media (RPMI, 10% FBS,Pen/Strep, L-glutamine, HEPES, non-essential amino acid, Sodiumpyruvate) with 100 ng/ml human GM-CSF (hu-GMCSF) and human IL-4(hu-IL-4) to differentiate dendritic cells for 6 days. Macrophages weredifferentiated for 5-6 days in complete media (RPMI, 10% FBS, Pen/Strep,L-glutamine, HEPES, non-essential amino acid, Sodium pyruvate) with 100ng/ml human hu-MCSF.

Anti-TREM2 antibodies or control antibody were added into a 96 wellplate and left at 4° C. overnight. The next day, the plate was washedtwice with PBS. Cells were plated at 25000 cells/well and cultured for 2days. Cells were then quantified using the CellTiter-Glo Luminescentcell viability kit (Promega) per manufacturer's protocol andluminescence was determined as a measure of cell viability.

Results

To test whether increased affinity correlates with enhanced function,affinity matured anti-TREM2 antibodies were tested first for theirability to trigger TREM2 signaling when added either soluble or platebound to BW cells expressing human TREM2/Dap12 and the NFAT:luciferasereporter. The parental AL2p antibody can cluster and activate TREM2signaling when added in a soluble solution to the cells or when bound tothe plate. In line with their increase in affinity, AL2p affinitymatured variant antibodies displayed enhanced ability to cluster andactivate TREM2, both in the plate bound and soluble format (Table 9A).Particularly in the plate bound format, affinity matured antibodiesstrongly enhanced NFAT:luciferase signaling compared to the parentalhumanized clones (Table 9A).

FIG. 3A and FIG. 3B show the results of functional analysis of AL2paffinity matured antibodies AL2p-58, AL2p-59, AL2p-60, AL2p-62, AL2p-47,and isotype control IgG antibody. As in Table 10A, antibodies weretested for their ability to induce TREM2 signaling in BW cellsexpressing NFAT:luciferase, added either soluble or plate bound.Antibody AL2p-58 is an affinity matured antibody derived from theAL2p-62 clone, but that includes light chain framework regions from twodifferent germlines (i.e., parental humanized anti-TREM2 antibodyclones). In particular, the AL2p-58 antibody has the light chainframework regions 1 and 2 (FR1 and FR2) from the AL2p-h77 germline andhas the light chain framework regions 3 and 4 (FR3 and FR4) from theAL2p-h50 germline. In contrast, all four light chain framework regionsof antibody AL2p-62 are from the AL2p-h77 germline. The results showthat antibody AL2p-58 has surprisingly good TREM2 signaling-inducingactivity, particularly as compared to the AL2p-62 antibody, despite bothantibodies sharing the same variable CDR's, except for CDR-H2 and CDR-L1(FIG. 3A and FIG. 3B). However, the differences with the CDR-H2 andCDR-L1 sequences of AL2p-58 and AL2p-62 are due to different hotfixes,which were not shown to positively or negatively affect antibodyaffinity or function (Table 9A). The results also indicate that whileAL2p-58 has the sane heavy chain variable region sequence as AL2p-37,AL2p-58 shows an unexpectedly high improvement in functional propertiescompared to AL2-p37.

The results in Table 10A also indicate that AL2p-47 shows surprisinglybetter functional properties, as well as higher affinity tocell-expressed TREM2, as compared to antibodies AL2p-45, AL2p-55, andAL2p-56, which all share the same light chain variable domain and verysimilar heavy chain variable domain sequences. In particular, the onlydifference in sequence between AL2p-47 and AL2p-45 is in the HVR-H2,where AL2p-47 has an H at the 16^(th) position and AL2p-45 has a Q(Table 2B). The differences in sequence between AL2-47 and AL2p-55 andAL2p-56 are a single amino acid difference in HVR-H1 (Table 2A), asingle amino acid difference in heavy chain FR1 (Table 4A), and a singleamino acid difference in HVR-H2, where AL2p-47 has an R at the 13^(th)position and both AL2p-55 and AL2p-56 have a Q (Table 2B). Based onthese results, it appears that the combination of the R at the 13^(th)position of the HVR-H2 sequence and the H at the 16^(th) position oHVR-H2 sequence of antibody AL2p-47 shows a surprising effect comparedto the R at the 13^(th) position alone (as is the case for AL2-p45) orthe H at the 16^(th) position alone (as is the case for AL2p-55 andAL2p-56), especially given that AL2p-47 has similar affinity to humanTREM2 protein as do AL2p-45, AL2p-55, and AL2p-56.

FIG. 3C shows the ability of plate bound affinity matured antibodyvariants to induce TREM2 signaling as measured by the NFAT:luciferasereporter assay. The results indicate a dramatic (up to 4-fold) increasein efficacy of affinity matured antibodies as compared to thecorresponding parental humanized AL2p antibody (h50 or h77) or theparental murine IgG1 antibody (AL2p).

TREM2 was shown to affect survival of primary murine macrophages andmicroglia in vitro, with TREM2 knock-out cells showing reduced viability(Wang et al., Cell 2015, 160(6):1061-1071). To verify functionality ofAL2p variant antibodies in primary cells, human monocyte derivedmacrophages or dendritic cells were stimulated with plate bound AL2pvariant antibodies and the viability of cells was measured 2 days later.It was found that plate bound AL2p parental antibody increases viabilityin a dose dependent fashion. Compared to the parental clone, affinitymatured AL2p variant antibodies increase viability even further (Tables9A and 10A).

Clones AL2p-23, AL2p-31 and AL2p-37 were produced in CHO cellscontaining the following variants: DG to EG and NG to NQ. These clonesretain the affinity of the parental clones (Table 9B).

TABLE 9A Functional analysis affinity matured antibodies LuciferaseLuciferase activation activation Survival huDCs soluble 10 plate bound33 plate bound IgG, Antibody nM IgG, FOC nM IgG, FOC AUC AL2p-h50 1.266.83 337353 AL2p-h77 1.47 6.77 380527 AL2p-2 1.70 7.36 461171 AL2p-31.29 6.03 363252 AL2p-4 1.45 7.42 495712 AL2p-5 1.27 9.99 709979 AL2p-61.20 5.39 546995 AL2p-7 2.35 18.87 n.d. AL2p-8 2.78 n.d. 1088000  AL2p-92.62 15.21 976481 AL2p-10 1.60 4.63 n.d. AL2p-11 1.71 23.64 n.d. AL2p-121.96 15.80 n.d. AL2p-13 2.17 16.53 n.d. AL2p-14 1.79 22.07 n.d. AL2p-151.80 7.54 487849 AL2p-16 2.60 16.87 880480 AL2p-17 2.13 23.83 n.d.AL2p-18 2.06 8.46 n.d. AL2p-19 2.06 25.85 n.d. AL2p-20 2.12 22.45 n.d.AL2p-21 1.83 13.05 n.d. AL2p-22 1.75 24.86 n.d. AL2p-23 2.53 29.751108000  AL2p-24 2.12 24.13 n.d. AL2p-25 2.35 22.28 n.d. AL2p-26 2.5925.91 1113000  AL2p-27 2.06 24.39 n.d. AL2p-28 2.14 9.27 n.d. AL2p-292.17 26.64 1113000  AL2p-30 2.31 15.78 n.d. AL2p-31 2.83 28.25 1209000 AL2p-32 1.47 4.90 n.d. AL2p-33 1.72 3.21 n.d. AL2p-35 2.05 5.15 453094AL2p-36 2.64 22.70 1143000  AL2p-37 2.16 9.42 679678

Table 9A shows a functional analysis of a set of AL2p affinity maturedantibodies, as compared to the parental antibodies AL2p-h50 andAL2p-h77. In the Table, n.d.=not determined; AUC=area under curve;FOC=fold over control, where the control is an isotype control antibody.Clones AL2p-2 to AL2p-6 are variants of parental antibody AL2p-h50 thatinclude hotfixes to eliminate a de-amidation site.

TABLE 9B Testing HVR variants for anti-TREM2 antibodies cell luciferaseVL- binding activation, VH-HVR2 HVR1 huT2 BW soluble IgG, Antibodyvariants variants K_(D) (M) EC₅₀ (M) AL2p-h50 none none  3.7E−016.31E−08 AL2p-h77 none none 3.90E−01 2.01E−08 AL2p-2 DG to GG none 2.2E−01 2.30E−08 AL2p-3 DG to EG none  2.3E−09 5.00E−08 AL2p-4 DG to QGnone  2.1E−09 6.62E−08 AL2p-5 none NG to NR  2.0E−09 3.81E−08 AL2p-6none NG to  4.2E−09 3.86E−08 NW AL2p-59 DG to EG NG to NQ 1.24E−091.12E−08 AL2p-60 GG to EG NG to NQ 1.12E−09 1.03E−08 AL2p-62 DG to EG NGto NQ 2.63E−09 2.51E−08 AL2p-31 DG to GG none 1.23E−09 6.92E−09**

In Table 9B, values marked with ** were obtained in a differentexperiment than the other values of the same column.

TABLE 10A Functional analysis of AL2p affinity matured antibodies thatinclude amino acid substitutions at positions susceptible tode-amidation BW Luc assay plate BW Luc assay DC Mac bound 7.3 nM IgG,soluble 7.3 nM IgG, viability viability Antibody FOC FOC (AUC) (AUC)AL2p-31 7.49 4.48 860213 83712 AL2p-38 4.47 4.98 785505 39036 AL2p-398.12 3.81 850801 66855 AL2p-40 8.49 9.92 824725 63235 AL2p-41 7.61 2.92859989 80670 AL2p-42 6.52 5.95 780879 57916 AL2p-43 5.41 8.84 n.d. n.d.AL2p-44 7.17 11.50 750071 74651 AL2p-45 2.29 2.38 543378 3676 AL2p-461.64 2.98 596898 6044 AL2p-47 3.54 3.48 771393 22055 AL2p-48 3.25 3.65769717 23589 AL2p-49 3.12 3.28 753554 15109 AL2p-50 1.19 2.07 286306−10420 AL2p-51 1.22 2.30 259485 −11153 AL2p-52 1.30 1.75 283169 −13548AL2p-53 1.45 2.32 234316 −10245 AL2p-54 1.53 2.17 569761 −7639 AL2p-551.49 2.08 630883 −5284 AL2p-56 1.51 2.02 643293 −7621 AL2p-57 1.41 2.03505964 −3564

Table 10A shows a functional analysis of AL2p affinity maturedantibodies from the second round of affinity maturation. Antibodies weretested for their ability to induce TREM2 signaling in BW cellsexpressing NFAT:luciferase, added either soluble or plate bound, as wellas their ability to increase viability of macrophages or dendritic cellsin a plate bound format. In Table 10A, n.d.=not determined; AUC=areaunder curve. DC=primary human dendritic cells; Mac=primary humanmacrophages; FOC=fold over control.

TABLE 10B Functional analysis of AL2p affinity matured antibody variantsluciferase activation, luciferase activation, Antibody soluble IgG, EC₅₀(nM) plate bound IgG, EC₅₀ (nM) AL2p 19.3 n.d. AL2p-31 1.14 10.1 AL2p-47104 206 AL2p-58 14 36

Table 10B and FIG. 4A and FIG. 4B show the results of functionalanalysis of parental mouse antibody AL2p, affinity matured antibodiesAL2p-31, AL2p-47, AL2p-58, and a control antibody. For antibodiesAL2p-31 and AL2p-58, the antibodies were generated using both a humanIgG constant region (huFC) or a mouse IgG constant region (msFc).Antibodies were tested for their ability to induce TREM2 signaling in BWcells expressing NFAT:luciferase, added either soluble or plate bound,as well as their ability to increase viability of macrophages ordendritic cells in a plate bound format. In Table 10B, n.d.=notdetermined. The results indicate that the affinity matured antibodieshad better TREM2 signaling-inducing activity and lower EC₅₀ than theparental mouse antibody AL2p (Table 10B and FIG. 4A and FIG. 4B).

Table 10C shows a comparison of antibody characteristics betweenaffinity matured antibodies AL2p-31, AL2p-47, and AL2p-58, and theparental mouse antibody AL2p.

TABLE 10C Comparison of affinity matured antibodies to parental murineantibody Characteristic AL2p AL2p-47 AL2p-31 AL2p-58 Germline MurineVH1-69; VH1-69; VH1-69; CK2D-29 CK2D-29 VK4-1/VK2D-29 Fab K_(D) (nM) to1.12 × 10⁻⁷ 1.27 × 10⁻⁸ 3.73 × 10⁻⁹ 1.33 × 10⁻⁸ recombinant hTREM2 Fabk_(on) (M) to 1.94 × 10⁵  2.67 × 10⁵  3.35 × 10⁵  3.26 × 10⁵ recombinant hTREM2 Fab k_(off) (M) to  3.4 × 10⁻³ 3.40 × 10⁻³ 1.26 ×10⁻³ 4.33 × 10⁻³ recombinant hTREM2 Binding to hTREM2 3.04   1.22  0.56 0.51 expressing cell line K_(D) (nM) Reporter assay plate Low 206.310.1 36.1 bound IgG (EC₅₀, nM) Reporter assay soluble 19    104.7 11.414.0 IgG (EC₅₀, nM) Dendritic cell viability −(1) +(2) ++(3) ++(3)

Example 4: PK/PD Analysis of Affinity Matured AL2p Antibodies

Methods

Human TREM2 transgenic (Tg) mice as well as wild-type (WT) littermatecontrols that only express murine TREM2 were used in a PK/PD study totest both the half-life of different AL2p affinity matured variantantibodies in the presence or absence of target engagement, as well asthe effect of AL2p antibody on soluble TREM2 in the plasma of TREM2 Tgmice.

Human TREM2 Tg mice were injected intraperitoneally on day 0 with 15mg/kg of HEK or CHO produced AL2p variants AL2p-31-HF as WT and PSEGhuIgG1, AL2p-23-HF, AL2p-37-HF, AL2p-58-HF, AL2p-40, AL2p-41, AL2p-47,all in a huIgG1 backbone, as well as control huIgG1 (n=2-3 mice/group).Human TREM2 Tg mice were injected intraperitoneally on day 0 with 15mg/kg of HEK or CHO produced AL2p variants AL2p-60 as PSEG huIgG1,AL2p-47 as huIgG1, AL2p-58 as huIgG1, as well as control huIgG1 (n=2-3mice/group). Blood was collected by tail vein puncture at the followingtime points: 4h after injection, days 1, 3, 6, 10 and 14. For plasmaisolation, the blood was collected in heparinized tubes and centrifugedat 10,000×g for 10 min at 4° C. Plasma supernatant was collected atstored at −80° C.

Levels of human IgG1 antibodies in the plasma were determined using acustom (MesoScale Discovery) MSD assay. Briefly, 96-well multi-arrayplates (MesoScale Discovery) were coated overnight at 4° C. with 50 μlof 1 μg/ml of goat anti-human Fab fragment specific for IgG (JacksonImmuno Research) at 500 rpm on a plate shaker. Plates were washed threetimes in 150 μl wash buffer (PBS+0.05% Tween) and blocked in bindingbuffer (PBS+1% BSA) for 1 hr at RT at 500 rpm on a plate shaker. Plasmawas diluted in binding buffer at 1:200 and 1:10,000 and added to theblocked plates and incubated for 1 h at 37° C. Control huIgG1 was usedas a standard. Plates were subsequently washed three times in 150 μlwash buffer and incubated with a goat anti-human sulfo-tag conjugatedsecondary antibody (MesoScale Discovery) at 1 μg/ml in binding bufferfor 1 hr at RT. Plates were subsequently washed three times in 150 μlwash buffer and 15 μl 1× Read Buffer was added to each well and theplates were imaged in a Sector Imager (MesoScale Discovery). Data wereanalyzed using GraphPad Prism.

For the human specific TREM2 ELISA, capture antibody T2KO8F11 was platedat 2 μg/ml in PBS overnight at 4 C (100 μL per well in high bind Elisaplates). The plates were washed thrice with a plate washer and 300 μLPBS+0.05% Triton per well. As a standard 156-10,000 pg/ml human TREM2-Fc(R&D Systems) was added to the plates, as well as diluted plasma samplesin binding buffer (PBS+1% BSA). Plates containing samples and standardwere incubated at RT for 1 hour. The plates were washed thrice with aplate washer and 300 μL PBS+0.05% Triton per well. Biotinylated goatanti-human TREM2 polyclonal antibody (R&D Systems) was added at 1:2,000dilution in binding buffer and incubated for 1 hour at RT. The plateswere washed thrice with a plate washer and 300 μL PBS+0.05% Triton perwell. Streptavidin-HRP (1:200 in binding buffer, R&D Systems) was addedto the plates and incubated for 20-30 minutes at RT. The plates werewashed thrice with a plate washer and 300 μL PBS+0.05% Triton per well.100 μL TMB substrate solution was added and incubated until colordeveloped. The reaction was stopped by adding 50 μL of 2N sulfuric acidand the plate was read in a Synergy H1 plate reader at 450 and 630 nm.Data were analyzed using GraphPad Prism.

Results

The half-life of AL2p variant antibodies was measured in human TREM2 Tgmice (Table 11). After injection of AL2p variant antibody, levels ofsTREM2 significantly decreased down to 65% of control levels andremained low for at least 6 days (Table 11). It is unclear what causesthis decrease. It could either be caused by AL2p blocking shedding ofsTREM2 or by AL2p causing internalization of TREM2 after inducingclustering. And these data suggest that sTREM2 levels in plasma or CSFcan be used as indicators for peripheral or brain target engagement invivo in patients.

TABLE 11 Parameters measured in vivo in human TREM2 Tg mice for controlhuIgG1 and AL2p affinity matured variant antibodies Estimated half-lifePlasma sTREM2 as % of Antibody (days) baseline on day 6 Control huIgG114.6 99.97 AL2p-60 1.5 51.75 huIgG1 PSEG AL2p-47 2.8 73.37 huIgG1AL2p-58 4.6 43.70 huIgG1

Example 5: Production and Testing of Fc Mutant Variants of TREM-2Agonistic Antibodies

Materials and Methods

Production of Fc Mutant Antibodies

Fc mutant antibodies were produced recombinantly via transienttransfection of HEK cells, and purification via Protein-A affinitycapture and size exclusion chromatography (SEC) polishing.

BWZ Reporter Assay

In addition to the BWZ reporter assays described in Examples 2 and 3,reporter cell assays for Fc-mutants were also carried out in co-culturewith various FcgR-expressing cell lines such as THP-1 or Raji. In thiscase, the assay was modified to include 10⁵ each of the reporter cellline as well as the FcgR-expressing line, in the same final volume ofmedia (100 μL per well). The two cell types were counted on a Vi-CELL XR(Beckman Coulter) and mixed in reporter cell media (DMEM+10% FBS)immediately prior to aliquoting into 96 well plates and addition ofantibody. The assay was then carried out in the same manner as describedpreviously (6 hour incubation with antibody at 37° C., followed bydetection of luciferase with the ONE-GLO reagent (Promega) and a BioTekplate reader).

Complement (C3b) Deposition Assay

The ability of anti-TREM2 antibodies to drive complement deposition wasmeasured on a stable HEK cell line overexpressing human TREM2 and DAP12,as well as on primary cells (monocyte-derived DCs). TREM2-expressingcells were diluted to 10^({circumflex over ( )}5) cells per 70 μL inmedia (DMEM+10% FBS for HEK, RPMI for DCs) and 70 μL of cells aliquotedper well in round-bottom 96 well plates (Falcon #351177). To these cellswas added 10 uL of 10× antibody diluted in the same media.Cells+antibody were incubated at 37° C. for 30 min, then 20 μL of pooledcomplement human serum (Innovative Research, IPLA-CSER) was added perwell as a complement source and the plates incubated for a further 2hours at 37° C. Afterwards, the cells were washed 2× with FACS buffer(PBS+2% FBS+1 mM EDTA), and 100 μL of 1:50 diluted anti-C3b-APC antibody(Biolegend 846106) was added per well and incubated on ice for 30minutes. The cells were then washed 2× with FACS buffer and resuspendedin 50 μL/well of FACS buffer+0.25 μL/well of propidium iodide (FischerScientific, BD 556463 prior to analysis on an iQue flow cytometer(IntelliCyt).

Production of Fc-Gamma-Receptor Detection Reagents

Human and mouse FcgR detection reagents were designed by fusing theextracellular domain of each FcgR with the C-terminal addition of anAVI/His tag to facilitate site-specific biotinylation and purification(Boesch et al, 2014). AVI-His FcgRs were produced by transienttransfection of HEK cells via and purified via immobilized metalaffinity chromatography (IMAC) capture followed by size exclusionchromatography (SEC) for polishing. Purified FcgRs were biotinylatedaccording to the conditions of the BirA biotin-protein ligase bulkreaction kit (Avidity). Tetrameric FcgR reagents were preparedimmediately prior to use by mixing 1 ug/mL of FcgR with a ¼^(th) molarratio of streptavidin-APC (eBioscience 17-4317-82) in FACS buffer andincubating for 10 min with rotation.

Fc-Gamma-Receptor Binding Assay

The ability of antigen-bound antibody to engage Fc receptors wasmeasured on the stable TREM2/DAP12 expressing HEK cell line. Briefly,TREM2-expressing cells were diluted to 100 k cells per 90 μL in media(DMEM+10% FBS for HEK) and 90 uL of cells aliquoted per well inround-bottom 96 well plates (Falcon). To these cells was added 10 μL of10× antibody diluted in the same media. Cells+antibody were incubated at37° C. for 1h to opsonize target cells, then the cells were washed 2× inFACS buffer, and 100 uL of the tetrameric FcgR detection reagent of FACSbuffer were added per well. Opsonized cells were incubated with FcgRtetramers for 1h at 4° C., and the cells were washed 2× with FACS bufferand resuspended in FACS buffer prior to analysis on an iQue flowcytometer (IntelliCyt).

Results

In the following example the sequence FC1 (human IgG1 Glm 17,1) was usedas the parental human IgG1 Fc and sequence FC10 was used as the parentalhuman IgG2 Fc for all further modifications.

Self-clustering Fc mutants that induce strong complement responses alsomay drive an agonistic response by inducing clustering (e.g., byinducing antibody multimerization), which can activate receptors;however, such mutants may also target the complement system towards thevery target cells from which the beneficial activity is being elicited.Therefore, combinations of Fc mutants were tested for ability to retainthe beneficial effects of clustering (e.g., hexamer-forming mutants)while reducing complement dependent cytotoxicity (CDC), for example byreducing the monomeric affinity to C1q.

Combinations of E430G with Fc mutants (e.g., K322A, A330S and P331S),which can reduce complement activation; as well as with other Fc mutants(e.g., combinations of L234A, L234F, L235A, L235E, and A330L) thatreduce binding to activating Fc-gamma-receptors (Armour et al, 2003;Idusogie et al, 2001) were tested in the context of anti-TREM2 antibodybinding.

BWZ Reporter Assay

Using the reporter-cell assay agonistic ability of the resultingantibodies was evaluated as well as their ability to drive complementactivation through CDC and C3b-deposition assays. E430G Fc variants ofan anti-TREM2 antibody strongly enhance agonistic activity, even in thepresence of compensatory mutations to remove C1q binding, such as P331S(FIG. 1A). To further probe these results, the ability of anti-TREM2antibodies to activate TREM2 in the presence of cell types bearing Fcgamma receptors was tested. Fc-gamma-receptor dependent clustering maybe an important mechanism for the activity of these antibodies in vivo,and as such should be retained if possible. In a co-culture system withTHP-1 cells (ATCC® TIB-202™), a monocytic leukemia cell line expressingseveral Fc gamma receptors, enhanced TREM2 signaling activity was seenfrom the humanized IgG1 variant (FIG. 1B). Adding in the E430G mutationfurther enhanced the activity, showing a possible additive orsynergistic effect of these two mechanisms. However, adding incompensatory mutations to fully remove Fc-receptor binding, such asLALAPS (L234A, L235A, P331S), also removed much of the benefit of usingE430G in this system.

Complement (C3b) Deposition Assay

E430G mutant can cause a strong increase in C3b deposition and CDC, overthe parental IgG1. This increase could be ameliorated following theaddition of compensatory mutations such as LALAPS (FIG. 2A). Various Fcmutant combinations of K322A, A330S and P331S together with E430G weretested for their ability to retain agonistic functionality (includingthrough FcgR-based mechanisms) while reducing complement activation.Inclusion of P331S alone with E430G (PSEG) was sufficient to reducecomplement activation below the level of that induced by the parentalIgG1 in one affinity-matured AL2p variant (FIG. 2B), while K322A andA330S had limited effect even in combination with P331S.

Fc-Gamma-Receptor Binding Assay

Fc mutant variants of AL2p leads are also tested for their ability toengage Fc-gamma-receptors. In this assay TREM-2 expressing cells areopsonized with anti-TREM2 antibodies and then a tetramerizedFcgR/streptavidin-APC probe is used to evaluate their ability to engageFcgRs. Both mouse and human FcgRs are tested.

Example 6: Improved Binding of Affinity Matured TREM2 Antibodies to BWCells Expressing Human TREM2

Materials and Methods

Binding assay: FACS-based cell binding was performed as described inExample 2.

Results

Side-by side comparison in binding was performed of the chimericparental AL2p antibody as huIgG1 and various humanized and affinitymatured variants thereof on either huIgG1 or huIgG1 PSEG Fc. AL2p-58 andAL2p-61 show a 2 to 3.6 fold increase in apparent affinity, while thereis not great affinity improvement by AL2p-37 and AL2p-47 on cellexpressed TREM2, despite both antibodies showing increased affinity torecombinant TREM2 (Table 12).

TABLE 12 Cell-based binding assay of high affinity binding of 9F5affinity matured variants Antibody ID Fc isotype Kd (nM) Bmax (MFI) AL2phuIgG1 1.32 199026 AL2p-58 huIgG1 0.63 196455 AL2p-58 huIgG1 PSEG 0.36140225 AL2p-37 huIgG1 1.17 216292 AL2p-47 huIgG1 1.20 226371 AL2p-61huIgG1 0.42 210636

Example 7: Improved Soluble and Plate Bound TREM2 Signaling ActivationUpon Affinity Maturation of AL2p

Materials and Methods

Luciferase assay—The ability of plate-bound or soluble, full-lengthanti-TREM2 antibodies to activate human TREM2-dependent genes wasevaluated using a luciferase reporter assay as described in Example 3.

Results

The ability of AL2p variant antibodies to activate TREM2-mediatedsignaling was tested in a heterologous NFAT:luciferase system. BW cellsexpress human TREM2/DAP12 chimera, as well as a NFAT:luciferase reportergene that is activated upon TREM2 clustering either by natural ligandsor TREM2 antibodies. Compared to AL2p, which had little stimulatoryactivity when plate bound, all affinity matured AL2p offspring, exceptfor AL2p-37, showed dramatic improvement in plate bound signalactivation, up to 10-fold over AL2p for AL2p-58 huIgG1 PSEG (Table 13).A similar improvement was observed for signaling activation by solubleIgG, where all affinity matured antibodies tested activated signalingwith a reduced EC50 and increased signaling levels compared to AL2p.

TABLE 13 Activation of TREM2 signaling in NFAT: luciferase expressing BWcells Plate bound IgG, Soluble IgG, fold over Soluble fold overunstimulated IgG, control control EC50 IgG Antibody ID Fc isotype (25 nMIgG) (nM) (17 nM IgG) AL2p huIgG1 1.29 14.59 4.51 AL2p-58 huIgG1 9.884.83 9.97 AL2p-58 huIgG1 PSEG 12.91 2.99 12.11 AL2p-37 huIgG1 1.56 9.417.63 AL2p-47 huIgG1 3.94 6.50 8.77 AL2p-61 huIgG1 8.97 5.24 10.75

Example 8: AL2p Variants Block Production of sTREM2 by Primary HumanDendritic Cells In Vitro

Materials and Methods

Generation of human dendritic cells and treatment with TREM2antibodies-Human monocytes were isolated from whole blood usingRosetteSep Human monocyte enrichment cocktail (Stemcell technologies)and Ficoll centrifugation per manufacturer protocols. After lysing redblood cells with ACK lysing buffer, monocytes were resuspended incomplete media (RPMI, 10% FBS, Pen/Strep, L-glutamine, HEPES,non-essential amino acid, Sodium pyruvate) with 100 ng/ml human GM-CSF(hu-GMCSF) and human IL-4 (hu-IL-4) to differentiate dendritic cells for6 days.

All suspended dendritic cells were harvested and tested for CD11cexpression by FACS staining Briefly, cells were washed in FACS buffer(PBS+2% FBS) and incubated with 1:5 dilution of anti-human CD11c-FITC orisotype control-FITC (BD Biosciences) for 1 hr on ice. Cells were washedwith 2 ml FACS buffer, pelleted by centrifugation and 250 ul FACS bufferwas added and cells were analyzed with a BD FACS Canto. For both donorstested, >90% of cells were CD11c positive and thus differentiated tohuman dendritic cells.

Harvested DC's were washed with PBS to remove cytokines, counted andplated at 100,000 cells/well in complete RPMI media in 96 well plates at50 ul. Cells were incubated at 37 C for one hour to let them settle andto block the plate with serum albumin. Thereafter, 50 ul of 2× antibodytitrations in RPMI were added to the plates. Cells were incubated for48h.

Cell supernatant was harvested to measure sTREM2. PBS+3 mM EDTA wasadded to the plates. Plates were incubated at 37 C for 5-10 minutes,until cells would go into suspension upon pipetting. Cells weretransferred to 96 well U-bottom plates, pelleted by centrifugation andresuspended in 45 ul FACS buffer and analyzed on iQE. Relative cellnumbers were measured by counting the number of cells in a fixed volumeof FACS buffer. Data were analyzed using Microsoft Excel and GraphPadPrism.

TREM2 MSD assay-A human TREM2-specific MSD assay was developed. Thecapture anti-TREM2 antibody T2KO811 was plated at 1 μg/ml in PBSovernight at 4 C (25 μL per well in single spot MSD plates, Meso ScaleDiscovery). The plates were washed thrice with a plate washer and 150 μLPBS+0.05% Triton per well. As a standard 100-0.02 ng/ml human TREM2-Fc(R&D Systems) was added to the plates, as well as cell supernatantdiluted in binding buffer (PBS+1% BSA), all at 50 ul per well. Platescontaining samples and standard were incubated at RT for 1 hour. Theplates were washed thrice with a plate washer and 150 μL PBS+0.05%Triton per well. Biotinylated goat anti-human TREM2 polyclonal antibody(R&D Systems) was added at 1:2,000 dilution in binding buffer andincubated for 1 hour at RT. The plates were washed thrice with a platewasher and 150 μL PBS+0.05% Triton per well. 25 μl sulfo-tag conjugatedStreptavidin (0.2 μg/ml in binding buffer, MesoScale Discovery) wasadded to the plates and incubated for 20 min at RT. The plates werewashed thrice with a plate washer and 150 μL PBS+0.05% Triton per well.150 μl of 1× Read Buffer (MesoScale Discovery) was added to each welland plates were read on a Sector Imager (MesoScale Discovery). Data wereanalyzed in Excel and Graph Pad Prism. It was tested whether AL2plineage antibodies interfere with the assay, by spiking the MSD assaywith different concentrations of AL2p variant antibodies. This had noeffect on signal levels measured, suggesting that there is no assayinterference by AL2p variant antibodies.

Results

TREM2 is produced as a cell surface receptor that can be cleaved torelease the extracellular domain. A rare TREM2 mutation in humans(H157Y) causes increased production of sTREM2 and increases the risk ofdevelopment of late onset Alzheimer's disease (Thornton et al, EMBO MolMed 2017, 9(10): 1366-78).

To test whether TREM2 antibodies block shedding of the receptor, sTREM2secreted into the media by primary human dendritic cells over the courseof 48h was measured by ELISA. Dendritic cells derived from monocytes oftwo human blood donors were tested, donor 534 and 535. The averageconcentration of sTREM2 for donor 534 was 97.0 ng/ml and for donor 53572.5 ng/ml. Upon addition of TREM2 antibodies sTREM2 secretion decreasedwith increasing antibody concentrations (FIG. 5A and FIG. 5B). Theweakest effect was observed by the parental AL2p antibody as a huIgG1chimera, although it did significantly reduce sTREM2 level at higherantibody concentrations in both donors. The humanized, affinity maturedvariant AL20-58 either as huIgG1 WT or PSEG showed the strongestdecrease at the lowest antibody concentration. Results were similaracross the two donors.

To test whether the reduction in sTREM2 was due to cell death andtherefore reduction in cell numbers, cell density after antibodyincubation was measured using iQE FACS analysis. There was no change incell numbers upon treatment of dendritic cells with TREM2 antibodies inneither of the two donors (FIG. 6A and FIG. 6B).

Example 9: TREM2 Agonistic Antibodies Increase Viability of PrimaryHuman Macrophages and Dendritic Cells

Methods

Human monocytes from three different donors were isolated from wholeblood using RosetteSep Human monocyte enrichment cocktail (Stemcelltechnologies) and Ficoll centrifugation per manufacturer protocols.After lysing red blood cells with ACK lysing buffer, monocytes wereresuspended in complete media (RPMI, 10% FBS, Pen/Strep, L-glutamine,HEPES, non-essential amino acid, Sodium pyruvate). For dendritic celldifferentiation, 100 ng/ml human GM-CSF (hu-GMCSF) and human IL-4(hu-IL-4) were added to the monocyte culture for six days. Formacrophage differentiation, 100 ng/ml human M-CSF (huM-CSF) was usedinstead.

For plate bound antibodies, one day before, 10 μg/ml anti-TREM2 orcontrol antibodies were added into a 96 well plate and left at 4° C.overnight. The next day, the plate was washed twice with PBS. Cells wereplated at 25000 cells/well without additional cytokines for human DCsand macrophages, and cultured for 2 days. For soluble antibodyconditions, antibodies were added to the media when the cells areplated. Cell viability was quantified using the CellTiter-GloLuminescent cell viability kit (Promega) per manufacturer's protocol andluminescence was measured using a Biotek Synergy H1 plate reader. Datawere analyzed using Microsoft Excel and GraphPad Prism.

Results

Both the parental AL2p antibody and its affinity matured offspring weretested for their ability to promote survival of primary human dendriticcells and macrophages. Cells were added to plates containing a titrationof plate bound antibodies, incubated for 48 hours and viability wasevaluated by measuring ATP content of the cells using CellTiterGlo(Promega).

Compared to the isotype control antibody, stimulating cells with TREM2antibodies increased viability of both primary human macrophages anddendritic cells in a dose dependent manner (FIG. 8A and FIG. 8B).Compared to the parental AL2p antibody, all affinity matured variantsshowed up to a several hundred-fold increase in efficacy, as evidencedby reduced half-maximal activity (see EC50 values in Table 14 (EC50values (nM) for different TREM2 antibodies in promoting viability ofprimary human macrophages or dendritic cells from three different donors(D558-560). P.F. denotes poor curve fit. All antibodies were tested ashuIgG1, with AL1p-58 also being tested as huIgG1 PSEG). The parentalAL2p antibody does show a dose dependent increase in viability, however,affinity matured versions of the antibody, especially AL2p-58 (both ashuIgG1 and huIgG1 PSEG), AL2p-47 and AL2p-60, show several hundred-foldlower EC50, suggesting a much higher potency. AL2p-37 still showed areduced EC50 compared to the parental IgG, but it is of lower potencythan the other antibodies.

In addition, the ability of antibody AL2p-58 to increase viability insoluble format was evaluated in a similar assay, but the antibody wasadded to the media when the cells were plated. Compared to isotypecontrol antibody, AL2p-58 was able to increase viability of both primaryhuman macrophages and dendritic cells (FIG. 8C-8F). These resultssuggest that antibody AL2p-58 will be functionally active in vivo.

TABLE 14 Macrophages Dendritic cells Antibody D558 D559 D560 D558 D559D560 AL2p 12.267 146.067 128.667 95.733 41.180 55.120 AL2p-58 0.0050.359 0.469 0.288 0.341 0.271 AL2p-58 PSEG 0.001 0.322 0.426 0.206 0.2760.206 AL2p-47 0.013 1.557 1.247 1.017 1.131 0.672 AL2p-60 P.F. 0.1940.154 0.152 0.244 0.178 AL2p-37 1.235 18.313 31.827 4.187 6.155 4.472

Example 10: AL2p Variants Reduce Levels of Plasma sTREM2 Levels In Vivo

Methods

In vivo procedures-Human TREM2 BAC Tg mice were group-housed inpolycarbonate cages and acclimated for at least 5 days prior tocommencing studies. Animals were maintained in a 12 hr light/dark cyclewith room temperature maintained at 22±2° C. and approximately 50%humidity, and received food and water ad libitum. For Experiments I-IIIanimals were injected I.P. or I.V. with AL2p-47 huIgG1, AL2p-47 huIgG1ASPSEG, AL2p-58 huIgG1, AL2p-58 huIgG1 PSEG, AL2p-61 huIgG1 PSEG orcontrol huIgG1 on day 0 and blood for plasma was collected inheparinized tubes 2-4 days prior to study initiation and on Days 0 (4hrs after injections), 1, 3, 6, 10 and 14. For Experiment IV, eitherAL2p msIgG1, T-21-9 msIgG1 or control msIgG1 were injected at 20 mg/kgI. P. on day 0 and plasma was collected on days 0 (4h after injection),2, 5, 8 and 14. Plasma was isolated by spinning blood samples for 5minutes at 5,000 rpm then collecting the supernatant. A total of four invivo experiments were performed: experiment I: n=3 animals/group;experiment II: n=10 animals/group; experiment III: n=4 animals/group;experiment IV: n=4 animals/group.

Human TREM2 MSD assay-Plasma sTREM2 was measured by MSD as outlined inExample 8.

Results

Affinity matured variants of AL2p were tested for their ability toreduce sTREM2 levels, based on in vitro experiments shown in Example 8that suggest AL2p antibodies block TREM2 shedding either directly byblocking binding of the ADAM sheddase or indirectly by inducing TREM2signal activation and endocytosis. Human TREM2 expressing BAC Tg micewere injected with 15 mg/kg IgG on day 0 and sTREM2 levels weremonitored over the course of 14 days and normalized to pre-treatmentbaseline. Table 15 outlines the % reduction in plasma sTREM2 observedafter treatment with the different AL2p variants and FIG. 7A-C showgraphs depicting reduction in sTREM2 after treatment of human BAC Tgmice with affinity matured versions of AL2p. In contrast, parental AL2phad no significant effect on plasma sTREM2 levels (FIG. 7D), whileanother TREM2 antibody that binds the Ig domain of the protein (T21-9)causes a several fold elevation of plasma sTREM2, likely because itstabilizes the protein. All variants induced reduction of sTREM2 forseveral days after treatment. AL2p-58 huIgG1 PSEG induced the strongestand longest lasting downregulation of sTREM2. These data suggest thatsTREM2 in both plasma and CSF can be used as a marker for targetengagement in vivo in human patients.

TABLE 15 Reduction in plasma sTREM2 after treatment with AL2p variantantibodies Antibody huIgG1 Expt. # 4 h, day 0 Day 1 Day 3 Day 6 Day 10Day 14 AL2p-47 WT I 102.9 88.3 74.6* 73.4** 87.7** 82.3 III 89.7 92.983.6* 91.5** 111.5 133.0 AL2p-47 ASPSEG III 103.1 107.5 93.5 97.5* 127.7150.8 AL2p-58 WT I 86.3 62.3**** 45.0**** 43.7**** 67.7**** 93.2 II85.0* 56.7**** 54.0**** 94.8 100.9 III 98.5 85.8* 58.0**** 59.4****79.9**** 131.9 AL2p-58 PSEG II 62.8**** 46.2**** 46.2**** 90.2* 113.2AL2p-61 PSEG I 74.2 57.8**** 47.4**** 51.8**** 98.2 88.2 Shown is %sTREM2 found in plasma of human TREM2 BAC Tg mice treated with differentTREM2 antibody variants either as huIgG1 WT or huIgG1 PSEG or huIgG1ASPSEG. Stars indicate values that are significantly lower compared tocontrol huIgG1 injected mice (*p < 0.05, **p < 0.01, ***p < 001, ****p <0.0001) using Two-way ANOVA and post hoc test for pairwise comparisons.

Example 11: AL2p Variants In Vivo

Methods

8 week old C57BL/6 (WT) or Bac-TG-hTREM2 mice were injected i.p. with 3ml of 3% thioglycollate. After 3 days, when the peritoneal cavity wasenriched with peritoneal macrophages (CD11b⁺F4/80⁺ expressing TREM2,mice were injected with huIgG1 or TREM2-specific antibodies AL2p-58huIgG1 or AL2p-58 huIgG1 (40 mg/kg). Peritoneal cells were recoveredafter one hour and immediately lysed in lysis buffer(n-dodecyl-b-malthoside 1%, 50 Mm Tris-HCl (pH 8.0), 150 mM NaCl, 1 mMEDTA, 1.5 mM MgCl₂, 10% glycerol, plus protease and phosphataseinhibitors), split after lysis and immunoprecipitated with rat anti-h/mTREM2 (RD, clone 237920) or isotype control. Precipitated proteins werefractionated by SDS-PAGE (non-reducing conditions), transferred tonitrocellulose membranes and probed with anti-phosphotyrosine antibody(Millipore, 4G10). To confirm that each cell lysate used for TREM2immunoprecipitations contained equal amount of proteins, an equal amountof lysates were collected before immunoprecipitation and fractionated bySDS-PAGE (reducing conditions). Immunoblots were probed with antibodiesdirected against human TREM2 (R&D #AF1828).

Results

TREM2 ligand binding induces receptor clustering, which triggersphosphorylation of its adaptor protein Dap12 and an intracellularsignaling cascade. To test if AL2p variant antibodies induce TREM2signal activation in vivo, WT or human TREM2 expressing Bac-Tg mice weretreated with thioglycollate to recruit macrophages to the peritoneum.After three days, mice were injected with anti-TREM2 or control huIgG1antibodies and subsequently, peritoneal macrophages were harvested,lysed and phosphorylation of Dap12 associated with TREM2 was probed as ameasure of TREM2 signaling activation.

Treatment of Bac-Tg mice with AL2p-58 huIgG1 or AL2p huIgG1 PSEG causeda strong increase in Dap12 phosphorylation compared to control huIgG1(FIG. 9). In contrast, the TREM2 antibodies showed no effect on Dap12 inWT mice, since these antibodies are not murine cross-reactive. Theseresults demonstrate that AL2p-58 antibodies can cluster and activate theTREM2 receptor in vivo.

Example 12: Unspecific Reactivity of AL2p Variants

Methods

A FACS-based assay to measure polyspecific reactivity (PSR) wasperformed as described in Xu et al., Protein Engineering, Design andSelection, 2013, 26 (10), 663-70. Results

While the parental humanized versions of AL2p (AL2p-h50, AL2p-h77) werePSR low, indicating that they do not unspecifically bind to non-TREM2targets, upon increasing affinity to TREM2 by affinity maturation, AL2pantibody variants showed elevated PSR values (Table 16). PSR positivelycorrelates with affinity and higher unspecific binding, which can resultin faster elimination of circulating antibody from the body and thus ashorter half-life. The results in Table 16, when combined with those inTables 9A-9C, 10A-10C, 11, 13 and 14 indicate that AL2p antibodyvariants with a high PSR have too short a half-life and AL2p antibodyvariants with low PSR do not exhibit sufficient functionality. However,AL2p antibody variants with medium PSR exhibit both low unspecificbinding and better functionality than AL2p antibody variants with lowPSR (Tables 9A-9C, 10A-10C, 13 and 14).

TABLE 16 Summary of PSR reactivity of AL2p variant antibodies AntibodyPSR value PSR range AL2p-h50 0.01 Low AL2p-h77 0.09 Low AL2p-2 0.10 LowAL2p-3 0.05 Low AL2p-4 0.10 Low AL2p-5 0.15 Low AL2p-6 0.10 Low AL2p-70.74 High AL2p-8 0.82 High AL2p-9 0.80 High AL2p-10 0.14 Low AL2p-110.68 High AL2p-12 0.57 Medium AL2p-13 0.71 High AL2p-14 0.80 HighAL2p-15 0.34 Medium AL2p-16 0.84 High AL2p-17 0.77 High AL2p-18 0.72High AL2p-19 0.84 High AL2p-20 0.74 High AL2p-21 0.75 High AL2p-22 0.88High AL2p-23 0.70 High AL2p-24 0.85 High AL2p-25 0.80 High AL2p-26 0.80High AL2p-27 0.87 High AL2p-28 0.52 Medium AL2p-29 0.72 High AL2p-300.70 High AL2p-31 0.85 High AL2p-32 0.10 Low AL2p-33 0.05 Low AL2p-350.10 Low AL2p-36 0.82 High AL2p-37 0.15 Low AL2p-38 0.73 High AL2p-390.66 High AL2p-40 0.69 High AL2p-41 0.77 High AL2p-42 0.76 High AL2p-430.70 High AL2p-44 0.67 High AL2p-45 0.33 Medium AL2p-46 0.44 MediumAL2p-47 0.48 Medium AL2p-48 0.55 Medium AL2p-49 0.54 Medium AL2p-50 0.16Low AL2p-51 0.20 Low AL2p-52 0.14 Low AL2p-53 0.22 Low AL2p-54 0.38Medium AL2p-55 0.37 Medium AL2p-56 0.37 Medium AL2p-57 0.42 MediumAL2p-59 n.d. AL2p-61 0.74 High AL2p-62 0.19 Low AL2p-58 0.59 Medium

SEQUENCES Human TREM2 protein (SEQ ID NO: 1)MEPLRLLILLFVTELSGAHNTTVFQGVAGQSLQVSCPYDSMKHWGRRKAWCRQLGEKGPCQRVVSTHNLWLLSFLRRWNGSTAITDDTLGGTLTITLRNLQPHDAGLYQCQSLHGSEADTLRKVLVEVLADPLDHRDAGDLWFPGESESFEDAHVEHSISRSLLEGEIPFPPTSILLLLACIFLIKILAASALWAAAWHGQKPGTHPPSELDCGHDPGYQLQTLPGLRDT Mouse TREM2 protein(SEQ ID NO: 2)MGPLHQFLLLLITALSQALNTTVLQGMAGQSLRVSCTYDALKHWGRRKAWCRQLGEEGPCQRVVSTHGVWLLAFLKKRNGSTVIADDTLAGTVTITLKNLQAGDAGLYQCQSLRGREAEVLQKVLVEVLEDPLDDQDAGDLWVPEESSSFEGAQVEHSTSRNQETSFPPTSILLLLACVLLSKFLAASILWAVARGRQKPGTPVVRGLDCGQDAGHQLQILTGPGGT Rat TREM2 protein(SEQ ID NO: 3)MEPLHVFVLLLVTELSQALNTTVLQGVAGQSLRVSCTYDALRHWGRRKAWCRQLAEEGPCQRVVSTHGVWLLAFLRKQNGSTVITDDTLAGTVTITLRNLQAGDAGLYQCQSLRGREAEVLQKVVVEVLEDPLDDQDAGDLWVPEESESFEGAQVEHSTSSQVSSCGSPLTYHLPPKEPIRKDLLPTHFHSSPPGLCPPEQASYSQHPLGCGQGQAEAGDTCGQWARL Rhesus monkey TREM2 protein(SEQ ID NO: 4)MPDPLFSAVQGKDKILHKALCICPWPGKGGMEPLRLLILLFATELSGAHNTTVFQGVEGQSLQVSCPYDSMKHWGRRKAWCRQLGEKGPCQRVVSTHNLWLLSFLRRRNGSTAITDDTLGGTLTITLRNLQPHDAGFYQCQSLHGSEADTLRKVLVEVLADPLDHRDAGDLWVPGESESFEDAHVEHSISRSLLEGEIPFPPTSVLLLLACIFLIKILAASALWAAAWHGQKPGTHPPSEPDCGHDPGHQLQTLPGLRDT Cynomolgus monkey TREM2 protein (SEQ ID NO: 5)MEPLRLLILLFATELSGAHNTTVFQGVEGQSLQVSCPYDSMKHWGRRKAWCRQLGEKGPCQRVVSTHNLWLLSFLRRRNGSTAITDDTLGGTLTITLRNLQPHDAGFYQCQSLHGSEADTLRKVLVEVLADPLDHRDAGDLWVPGESESFEDAHVEHSISRSLLEGEIPFPPTSVLLLLACIFLIKILAASALWAAAWHGQKPGTHPPSEPDCGHDPGHQLQTLPGLRDT Equine TREM2 protein(SEQ ID NO: 6)MEPLPLLILLSVAELSRGHNTTVFQGTAGRSLKVSCPYNSLMHWGRRKAWCRQLGEDGPCQQVVSTHSLWLLSFLKRRNGSTVITDDALGGILTITLRNLQAHDAGFYQCQSLHGGEADTLRKVLVEVLADPLDHQEPGDLWIPKESESFEDAQVEHSISRSLVEEEIPSLPTSILLLLACIFLSKLLAASAIWAAAWHGQKQETPPASEPDRGHDPGYQLHTLTGERDT Pig TREM2 protein(SEQ ID NO: 7)METLGLLLLLWVAELSRAHNTSVFQGTAGQSLRVSCSYNSLKHWGRRKAWCRQLSEEGLCQHVVSTHPTWLLSFLKRRNGSTAITDDALGGTLTITLRNLQAHDAGLYQCQSLHGSEADTLKKVLVEVLADPLESQSKSFQDVQMEHSISRNLSEESLFPPTSTLFLLACVFLSKLLVASALWAAAWHGHKQRTSPAGGLDCGRDPGDQDQTLTDELGESSDQDQTLTELRDT Dog TREM2 protein(SEQ ID NO: 8)MEPLWLLILLAVTELSGAHNTTVFQGMAGRSLQVSCPYNSLKHWGRRKAWCRQVDKEGPCQRVVSTHRSWLLSFLKRWNGSTAIVDDALGGTLTITLRNLQAHDAGLYQCQSLYGDEADTLRKVLVEVLADPLDHLDPGDLWIPEESKGFEDAHVEPSVSRSLSEEEIPFPPTSILFLLACIFLSKFLAASALWAAAWRGQKLGTPQASELDCSCDPGYQLQTLTEPRDMParental mouse AL2p heavy chain variable region (SEQ ID NO: 119)QVQLQQSGPELVKPGASLKISCKASGYAFSSSWMNWVKQRPGKGLEWIGRIYPGDGDTNYNGEFRVRATLTADTSSTTAYMQLSSLTSEDSAVYFCARLLRNQPGESYAMDYWGQGASVTVS SParental mouse AL2p light chain variable region (SEQ ID NO: 120)DVVMTQTPLSLPVSLGDQASISCRSSQSLVHSNGYTYLHWYLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEADDLGVYFCSQSTRVPYTFGGGTKLEIKFC1 (wild-type human IgG1) (SEQ ID NO: 146)ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK FC2 (IgG1 E430G) (SEQ ID NO: 147)ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK FC3 (IgG1 L234A, L235A, P331S: LALAPS)(SEQ ID NO: 148)ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK FC4 (IgG1 L234A, L235A, P331S, E430G: LALAPSEG)(SEQ ID NO: 149)ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPASIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK FC5 (IgG1 K322A, E430G: KAEG) (SEQ ID NO: 150)ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK FC6 (IgG1 P331S, E430G: PSEG) (SEQ ID NO: 151)ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK FC7 (IgG1 A3305, P331S, E430G: ASPSEG)(SEQ ID NO: 152)ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPSSIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK FC8 (IgG1 K322A, P331S, E430G: KAPSEG)(SEQ ID NO: 153)ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCAVSNKALPASIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK FC9 (wild-type human IgG2) (SEQ ID NO: 154)ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK FC10 (IgG2 E430G) (SEQ ID NO: 155)ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPAPIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK FC11 (IgG2 A330S P331S E430G: ASPSEG) (SEQ ID NO: 156)ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSNFGTQTYTCNVDHKPSNTKVDKTVERKCCVECPPCPAPPVAGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKGLPSSIEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHGALHNHYTQKSLSLSPGK

What is claimed is:
 1. An antibody that binds to a human TREM2 protein, wherein the antibody comprises a heavy chain variable region comprising an HVR-H1, HVR-H2, and HVR-H3 and a light chain variable region comprising an HVR-L1, HVR-L2, and HVR-L3, wherein the HVR-H1 comprises the sequence of SEQ ID NO: 132, the HVR-H2 comprises the sequence of SEQ ID NO: 135, the HVR-H3 comprises the sequence of SEQ ID NO: 126, the HVR-L1 comprises the sequence of SEQ ID NO: 144, the HVR-L2 comprises the sequence of SEQ ID NO: 131, and the HVR-L3 comprises the sequence of SEQ ID NO:
 129. 2. The antibody of claim 1, wherein the antibody binds to one or more human TREM2 proteins selected from the group consisting of wild-type human TREM2, a naturally occurring variant of human TREM2, and a disease variant of human TREM2.
 3. The antibody of claim 1, wherein the antibody is an antibody fragment selected from an Fab, Fab′, Fab′-SH, F(ab′)2, Fv, scFv, or an antibody fragment comprising an antigen binding region.
 4. The antibody of claim 1, wherein the antibody is a monoclonal antibody.
 5. The antibody of claim 1, wherein the antibody is a humanized antibody.
 6. The antibody of claim 1, wherein the antibody is of the IgG class, the IgM class, or the IgA class.
 7. The antibody of claim 6, wherein the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.
 8. The antibody of claim 7, wherein the antibody comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: C127S, L234A, L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S, E345R, E430G, S440Y, and any combination thereof, wherein the numbering of the residues is according to EU numbering.
 9. The antibody of claim 7, wherein the antibody has an IgG1 or IgG2 isotype, and wherein: the Fc region comprises an amino acid substitution at positions E430G, L234A, L235A, and P331S, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions E430G and P331S, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions E430G and K322A, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions E430G, A330S, and P331S, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions E430G, K322A, A330S, and P331S, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions E430G, K322A, and A330S, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions E430G, K322A, and P331S, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions S267E and L328F, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at position C127S, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions E345R, E430G and S440Y, wherein the numbering of the residue position is according to EU numbering; or the Fc region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 146-156.
 10. The antibody of claim 9, wherein the antibody has an IgG1 isotype, and wherein the Fc region comprises an amino acid substitution at positions E430G and P331S, wherein the numbering of the residue position is according to EU numbering.
 11. The antibody of claim 1, wherein the antibody is a bispecific antibody recognizing a first antigen and a second antigen, wherein the first antigen is human TREM2 or a naturally occurring variant thereof, and the second antigen is: (a) an antigen facilitating transport across the blood-brain-barrier; (b) an antigen facilitating transport across the blood-brain-barrier selected from the group consisting of transferrin receptor (TR), insulin receptor (HIR), insulin-like growth factor receptor (IGFR), low-density lipoprotein receptor related proteins 1 and 2 (LPR-1 and 2), diphtheria toxin receptor, CRM197, a llama single domain antibody, TMEM 30(A), a protein transduction domain, TAT, Syn-B, penetratin, a poly-arginine peptide, an angiopeptide, and ANG1005; (c) a disease-causing agent selected from the group consisting of disease-causing peptides or proteins or, disease-causing nucleic acids, wherein the disease-causing nucleic acids are antisense GGCCCC (G2C4) repeat-expansion RNA, the disease-causing proteins are selected from the group consisting of amyloid beta, oligomeric amyloid beta, amyloid beta plaques, amyloid precursor protein or fragments thereof, Tau, IAPP, alpha-synuclein, TDP-43, FUS protein, C9orf72 (chromosome 9 open reading frame 72), c9RAN protein, prion protein, PrPSc, huntingtin, calcitonin, superoxide dismutase, ataxin, ataxin 1, ataxin 2, ataxin 3, ataxin 7, ataxin 8, ataxin 10, Lewy body, atrial natriuretic factor, islet amyloid polypeptide, insulin, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, S-IBM protein, Repeat-associated non-ATG (RAN) translation products, DiPeptide repeat (DPR) peptides, glycine-alanine (GA) repeat peptides, glycine-proline (GP) repeat peptides, glycine-arginine (GR) repeat peptides, proline-alanine (PA) repeat peptides, ubiquitin, and proline-arginine (PR) repeat peptides; (d) ligands and/or proteins expressed on immune cells, wherein the ligands and/or proteins selected from the group consisting of CD40, OX40, ICOS, CD28, CD137/4-1BB, CD27, GITR, PD-L1, CTLA-4, PD-L2, PD-1, B7-H3, B7-H4, HVEM, BTLA, KIR, GALS, TIM3, A2AR, LAG-3, and phosphatidylserine; and (e) a protein, lipid, polysaccharide, or glycolipid expressed on one or more tumor cells.
 12. The antibody of claim 1, wherein the antibody binds specifically to both human TREM2 and cynomolgus monkey TREM2.
 13. The antibody of claim 12, wherein the antibody has a dissociation constant (K_(D)) for cynomolgus monkey TREM2 that ranges from about 100 pM to about 50 nM, wherein the K_(D) is determined at a temperature of approximately 25° C.
 14. The antibody of claim 1, wherein the antibody binds to primary human immune cells with an affinity that is at least 10 times higher than that of an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 27 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 92; or at least 10 times higher than an anti-TREM2 antibody comprising a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 56 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:
 104. 15. The antibody of claim 1, wherein the antibody clusters and activates TREM2 signaling in an amount that is greater than that of a human control IgG1 antibody.
 16. The antibody of claim 1, wherein the antibody increases immune cell survival in vitro to an extent that is greater than a human control IgG1 antibody.
 17. The antibody of claim 1, wherein the antibody has an in vivo half-life that is lower than a human control IgG1 antibody.
 18. The antibody of claim 1, wherein the antibody decreases plasma levels of soluble TREM2 in vivo by at least 25% compared to a human control IgG1 antibody.
 19. The antibody of claim 18, wherein the antibody decreases plasma levels of soluble TREM2 in vivo by blocking cleavage and/or by inducing internalization.
 20. A pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier.
 21. An isolated nucleic acid comprising a nucleic acid sequence encoding the antibody of claim
 1. 22. A vector comprising the nucleic acid of claim
 21. 23. An isolated host cell comprising the vector of claim
 22. 24. A method of producing an antibody that binds to TREM2, comprising culturing the cell of claim 23 so that the antibody is produced.
 25. The method of claim 24, further comprising recovering the antibody produced by the cell.
 26. An isolated antibody that binds to TREM2 produced by the method of claim
 25. 27. An antibody that binds to a human TREM2 protein, wherein the antibody comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 59 and a light chain variable region comprising the amino acid sequence of SEQ ID NO:
 112. 28. The antibody of claim 27, wherein the antibody binds to one or more human TREM2 proteins selected from the group consisting of wild-type human TREM2, a naturally occurring variant of human TREM2, and a disease variant of human TREM2.
 29. The antibody of claim 27, wherein the antibody is an antibody fragment selected from an Fab, Fab′, Fab′-SH, F(ab′)2, Fv or scFv, or an antibody fragment comprising an antigen binding region.
 30. The antibody of claim 27, wherein the antibody is a monoclonal antibody.
 31. The antibody of claim 27, wherein the antibody is of the IgG class, the IgM class, or the IgA class.
 32. The antibody of claim 31, wherein the antibody is of the IgG class and has an IgG1, IgG2, IgG3, or IgG4 isotype.
 33. The antibody of claim 32, wherein the antibody comprises one or more amino acid substitutions in the Fc region at a residue position selected from the group consisting of: C127S, L234A, L234F, L235A, L235E, S267E, K322A, L328F, A330S, P331S, E345R, E430G, S440Y, and any combination thereof, wherein the numbering of the residues is according to EU numbering.
 34. The antibody of claim 32, wherein the antibody has an IgG1 or IgG2 isotype, and wherein: the Fc region comprises an amino acid substitution at positions E430G, L234A, L235A, and P331S, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions E430G and P331S, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions E430G and K322A, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions E430G, A330S, and P331S, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions E430G, K322A, A330S, and P331S, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions E430G, K322A, and A330S, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions E430G, K322A, and P331S, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions S267E and L328F, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at position C127S, wherein the numbering of the residue position is according to EU numbering; the Fc region comprises an amino acid substitution at positions E345R, E430G and S440Y, wherein the numbering of the residue position is according to EU numbering; or the Fc region comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 146-156.
 35. The antibody of claim 34, wherein the antibody has an IgG1 isotype, and wherein the Fc region comprises an amino acid substitution at positions E430G and P331S, wherein the numbering of the residue position is according to EU numbering.
 36. A pharmaceutical composition comprising the antibody of claim 27 and a pharmaceutically acceptable carrier.
 37. An isolated nucleic acid comprising a nucleic acid sequence encoding the antibody of claim
 27. 38. A vector comprising the nucleic acid of claim
 37. 39. An isolated host cell comprising the vector of claim
 38. 40. A method of producing an antibody that binds to TREM2, comprising culturing the cell of claim 39 so that the antibody is produced.
 41. The method of claim 40, further comprising recovering the antibody produced by the cell.
 42. An isolated antibody that binds to TREM2 produced by the method of claim
 41. 43. An antibody that binds to a human TREM2 protein, comprising a heavy chain and a light chain, wherein: (a) the heavy chain comprises the amino acid sequence of SEQ ID NO: 198, and the light chain comprises the amino acid sequence of SEQ ID NO: 214; (b) the heavy chain comprises the amino acid sequence of SEQ ID NO: 199, and the light chain comprises the amino acid sequence of SEQ ID NO: 214; (c) the heavy chain comprises the amino acid sequence of SEQ ID NO: 200, and the light chain comprises the amino acid sequence of SEQ ID NO: 214; or (d) the heavy chain comprises the amino acid sequence of SEQ ID NO: 201, and the light chain comprises the amino acid sequence of SEQ ID NO:
 214. 44. A pharmaceutical composition comprising the antibody of claim 43 and a pharmaceutically acceptable carrier.
 45. A monoclonal antibody that binds to a human TREM2 protein, wherein the antibody comprises a heavy chain and a light chain, and wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 200 and the light chain comprises the amino acid sequence of SEQ ID NO:
 214. 46. A pharmaceutical composition comprising the antibody of claim 45 and a pharmaceutically acceptable carrier.
 47. An isolated nucleic acid comprising a nucleic acid sequence encoding the antibody of claim
 45. 48. A vector comprising the nucleic acid of claim
 47. 49. An isolated host cell comprising the vector of claim
 48. 50. A method of producing an antibody that binds to TREM2, comprising culturing the cell of claim 49 so that the antibody is produced.
 51. The method of claim 50, further comprising recovering the antibody produced by the cell.
 52. An isolated antibody that binds to TREM2 produced by the method of claim
 51. 53. A monoclonal antibody that binds to a human TREM2 protein, wherein the antibody comprises a heavy chain and a light chain, and wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 201 and the light chain comprises the amino acid sequence of SEQ ID NO:
 214. 54. A pharmaceutical composition comprising the antibody of claim 53 and a pharmaceutically acceptable carrier.
 55. An isolated nucleic acid comprising a nucleic acid sequence encoding the antibody of claim
 53. 56. A vector comprising the nucleic acid of claim
 55. 57. An isolated host cell comprising the vector of claim
 56. 58. A method of producing an antibody that binds to TREM2, comprising culturing the cell of claim 57 so that the antibody is produced.
 59. The method of claim 58, further comprising recovering the antibody produced by the cell.
 60. An isolated antibody that binds to TREM2 produced by the method of claim
 59. 